FREE SHIPPING over $40
Horse Supplements USA English
Horse Supplements Canada EnglishSuppléments Équins Canada French
My Account
View Cart My Horses Track Orders Account Details My Subscriptions Update Address Payment Methods
Register/Login
0
Home/Equine Research Bank/Proc Natl Acad Sci U S A/Deubiquitinase function of arterivirus papain-like protease ...
Proceedings of the National Academy of Sciences of the United States of America2013; 110(9); E838-E847; doi: 10.1073/pnas.1218464110

Deubiquitinase function of arterivirus papain-like protease 2 suppresses the innate immune response in infected host cells.

Abstract: Protein ubiquitination regulates important innate immune responses. The discovery of viruses encoding deubiquitinating enzymes (DUBs) suggests they remove ubiquitin to evade ubiquitin-dependent antiviral responses; however, this has never been conclusively demonstrated in virus-infected cells. Arteriviruses are economically important positive-stranded RNA viruses that encode an ovarian tumor (OTU) domain DUB known as papain-like protease 2 (PLP2). This enzyme is essential for arterivirus replication by cleaving a site within the viral replicase polyproteins and also removes ubiquitin from cellular proteins. To dissect this dual specificity, which relies on a single catalytic site, we determined the crystal structure of equine arteritis virus PLP2 in complex with ubiquitin (1.45 Å). PLP2 binds ubiquitin using a zinc finger that is uniquely integrated into an exceptionally compact OTU-domain fold that represents a new subclass of zinc-dependent OTU DUBs. Notably, the ubiquitin-binding surface is distant from the catalytic site, which allowed us to mutate this surface to significantly reduce DUB activity without affecting polyprotein cleavage. Viruses harboring such mutations exhibited WT replication kinetics, confirming that PLP2-mediated polyprotein cleavage was intact, but the loss of DUB activity strikingly enhanced innate immune signaling. Compared with WT virus infection, IFN-β mRNA levels in equine cells infected with PLP2 mutants were increased by nearly an order of magnitude. Our findings not only establish PLP2 DUB activity as a critical factor in arteriviral innate immune evasion, but the selective inactivation of DUB activity also opens unique possibilities for developing improved live attenuated vaccines against arteriviruses and other viruses encoding similar dual-specificity proteases.
Get Full Text
Publication Date: 2013-02-11 PubMed ID: 23401522PubMed Central: PMC3587229DOI: 10.1073/pnas.1218464110Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedIn
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study examines how the papain-like protease 2 (PLP2), a deubiquitinating enzyme found in arteriviruses, suppresses a host cell’s innate immune response. By manipulating a specific element of PLP2, the researchers could enhance the immune response to the virus. This could potentially lead to the development of more effective vaccines for arteriviruses and similar viruses.

Understanding Ubiquitin and Deubiquitinating Enzymes

  • Protein ubiquitination is a process that regulates key aspects of an organism’s innate immune response.
  • Some viruses encode deubiquitinating enzymes (DUBs) that remove ubiquitin, which is believed to help these viruses evade ubiquitin-dependent antiviral responses. This behavior has never previously been conclusively observed in cells infected by a virus.

The Role of PLP2 in Arterivirus Replication

  • Arteriviruses, which are economically impactful positive-stranded RNA viruses, encode a DUB with an ovarian tumor (OTU) domain known as papain-like protease 2 (PLP2).
  • PLP2 is vital for arterivirus replication; it cleaves a site within the viral replicase polyproteins and removes ubiquitin from cellular proteins.

Observations from the Crystal Structure of PLP2

  • The researchers identified the crystal structure of equine arteritis virus PLP2 in complex with ubiquitin.
  • PLP2’s ability to cleave polyproteins and remove ubiquitin depends on a single catalytic site. It was found to use a zinc finger that is integrated uniquely into a compact OTU-domain fold, marking a new subclass of zinc-dependent OTU DUBs.

Manipulating PLP2’s Ubiquitin-Binding Surface

  • The researchers found that the PLP2’s ubiquitin-binding surface is distant from the catalytic site. This distinction allowed them to mutate the ubiquitin-binding surface, significantly reducing DUB activity without impacting polyprotein cleavage.
  • The researchers observed that the viruses carrying these mutations exhibited normal replication kinetics, confirming that polyprotein cleaving process was still intact. However, it was found that the loss of DUB activity significantly improved innate immune signaling.

Conclusion: PLP2 DUB Activity as a Factor in Immune Evasion

  • Compared to a regular virus infection, cells infected with the manipulated PLP2 showed nearly ten times the level of IFN-β mRNA, pointing to a strong immune response.
  • The study helped establish the critical role of PLP2 DUB activity in allowing arteriviruses to skirt innate immune defenses. The researchers also found that selectively disabling DUB activity could open up new possibilities for creating more effective live attenuated vaccines against arteriviruses and other viruses that encode similar dual-specific proteases.

Cite This Article

APA
van Kasteren PB, Bailey-Elkin BA, James TW, Ninaber DK, Beugeling C, Khajehpour M, Snijder EJ, Mark BL, Kikkert M. (2013). Deubiquitinase function of arterivirus papain-like protease 2 suppresses the innate immune response in infected host cells. Proc Natl Acad Sci U S A, 110(9), E838-E847. https://doi.org/10.1073/pnas.1218464110

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 110
Issue: 9
Pages: E838-E847

Researcher Affiliations

van Kasteren, Puck B
  • Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
Bailey-Elkin, Ben A
    James, Terrence W
      Ninaber, Dennis K
        Beugeling, Corrine
          Khajehpour, Mazdak
            Snijder, Eric J
              Mark, Brian L
                Kikkert, Marjolein

                  MeSH Terms

                  • Animals
                  • Coronavirus Papain-Like Proteases
                  • Endopeptidases / chemistry
                  • Endopeptidases / genetics
                  • Endopeptidases / metabolism
                  • Equartevirus / enzymology
                  • Equartevirus / physiology
                  • Fibroblasts / immunology
                  • Fibroblasts / virology
                  • HEK293 Cells
                  • Hemorrhagic Fever Virus, Crimean-Congo / enzymology
                  • Horses
                  • Host-Pathogen Interactions / immunology
                  • Humans
                  • Immunity, Innate
                  • Interferon-beta / genetics
                  • Models, Molecular
                  • Mutation / genetics
                  • Papain / chemistry
                  • Papain / genetics
                  • Papain / metabolism
                  • Promoter Regions, Genetic / genetics
                  • Protein Binding
                  • Protein Structure, Tertiary
                  • Saccharomyces cerevisiae / enzymology
                  • Signal Transduction / immunology
                  • Substrate Specificity
                  • Ubiquitin / chemistry
                  • Virus Replication
                  • Zinc Fingers

                  Grant Funding

                  • Canadian Institutes of Health Research

                  Conflict of Interest Statement

                  Conflict of interest statement: The authors have filed a provisional patent application that relates to some aspects of this work.

                  References

                  This article includes 84 references
                  1. Firth AE, Brierley I. Non-canonical translation in RNA viruses.. J Gen Virol 2012 Jul;93(Pt 7):1385-1409.
                    pmc: PMC3542737pubmed: 22535777doi: 10.1099/vir.0.042499-0google scholar: lookup
                  2. Dougherty WG, Semler BL. Expression of virus-encoded proteinases: functional and structural similarities with cellular enzymes.. Microbiol Rev 1993 Dec;57(4):781-822.
                    pmc: PMC372939pubmed: 8302216doi: 10.1128/mr.57.4.781-822.1993google scholar: lookup
                  3. Gorbalenya AE, Donchenko AP, Blinov VM, Koonin EV. Cysteine proteases of positive strand RNA viruses and chymotrypsin-like serine proteases. A distinct protein superfamily with a common structural fold.. FEBS Lett 1989 Jan 30;243(2):103-14.
                    pubmed: 2645167doi: 10.1016/0014-5793(89)80109-7google scholar: lookup
                  4. Gorbalenya AE, Koonin EV, Lai MM. Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha- and coronaviruses.. FEBS Lett 1991 Aug 19;288(1-2):201-5.
                    pmc: PMC7130274pubmed: 1652473doi: 10.1016/0014-5793(91)81034-6google scholar: lookup
                  5. Hellen CU, Kru00e4usslich HG, Wimmer E. Proteolytic processing of polyproteins in the replication of RNA viruses.. Biochemistry 1989 Dec 26;28(26):9881-90.
                    pubmed: 2695162doi: 10.1021/bi00452a001google scholar: lookup
                  6. Etchison D, Milburn SC, Edery I, Sonenberg N, Hershey JW. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex.. J Biol Chem 1982 Dec 25;257(24):14806-10.
                    pubmed: 6294080
                  7. Kru00e4usslich HG, Nicklin MJ, Toyoda H, Etchison D, Wimmer E. Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220.. J Virol 1987 Sep;61(9):2711-8.
                    pmc: PMC255777pubmed: 3039165doi: 10.1128/JVI.61.9.2711-2718.1987google scholar: lookup
                  8. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.. Proc Natl Acad Sci U S A 2005 Dec 6;102(49):17717-22.
                    pmc: PMC1308909pubmed: 16301520doi: 10.1073/pnas.0508531102google scholar: lookup
                  9. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.. Nature 2005 Oct 20;437(7062):1167-72.
                    pubmed: 16177806doi: 10.1038/nature04193google scholar: lookup
                  10. Ventoso I, MacMillan SE, Hershey JW, Carrasco L. Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex.. FEBS Lett 1998 Sep 11;435(1):79-83.
                    pubmed: 9755863doi: 10.1016/s0014-5793(98)01027-8google scholar: lookup
                  11. Balasuriya UB, MacLachlan NJ. The immune response to equine arteritis virus: potential lessons for other arteriviruses.. Vet Immunol Immunopathol 2004 Dec 8;102(3):107-29.
                    pubmed: 15507299doi: 10.1016/j.vetimm.2004.09.003google scholar: lookup
                  12. Huang YW, Meng XJ. Novel strategies and approaches to develop the next generation of vaccines against porcine reproductive and respiratory syndrome virus (PRRSV).. Virus Res 2010 Dec;154(1-2):141-9.
                    pmc: PMC7132426pubmed: 20655962doi: 10.1016/j.virusres.2010.07.020google scholar: lookup
                  13. Fang Y, Snijder EJ. The PRRSV replicase: exploring the multifunctionality of an intriguing set of nonstructural proteins.. Virus Res 2010 Dec;154(1-2):61-76.
                    pmc: PMC7114499pubmed: 20696193doi: 10.1016/j.virusres.2010.07.030google scholar: lookup
                  14. Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales.. J Gen Virol 2000 Apr;81(Pt 4):853-79.
                    pubmed: 10725411doi: 10.1099/0022-1317-81-4-853google scholar: lookup
                  15. Han J, Rutherford MS, Faaberg KS. The porcine reproductive and respiratory syndrome virus nsp2 cysteine protease domain possesses both trans- and cis-cleavage activities.. J Virol 2009 Sep;83(18):9449-63.
                    pmc: PMC2738230pubmed: 19587037doi: 10.1128/JVI.00834-09google scholar: lookup
                  16. Snijder EJ, Wassenaar AL, Spaan WJ, Gorbalenya AE. The arterivirus Nsp2 protease. An unusual cysteine protease with primary structure similarities to both papain-like and chymotrypsin-like proteases.. J Biol Chem 1995 Jul 14;270(28):16671-6.
                    pubmed: 7622476doi: 10.1074/jbc.270.28.16671google scholar: lookup
                  17. Posthuma CC, Pedersen KW, Lu Z, Joosten RG, Roos N, Zevenhoven-Dobbe JC, Snijder EJ. Formation of the arterivirus replication/transcription complex: a key role for nonstructural protein 3 in the remodeling of intracellular membranes.. J Virol 2008 May;82(9):4480-91.
                    pmc: PMC2293027pubmed: 18305048doi: 10.1128/JVI.02756-07google scholar: lookup
                  18. Frias-Staheli N, Giannakopoulos NV, Kikkert M, Taylor SL, Bridgen A, Paragas J, Richt JA, Rowland RR, Schmaljohn CS, Lenschow DJ, Snijder EJ, Garcu00eda-Sastre A, Virgin HW 4th. Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses.. Cell Host Microbe 2007 Dec 13;2(6):404-16.
                    pmc: PMC2184509pubmed: 18078692doi: 10.1016/j.chom.2007.09.014google scholar: lookup
                  19. Behrends C, Harper JW. Constructing and decoding unconventional ubiquitin chains.. Nat Struct Mol Biol 2011 May;18(5):520-8.
                    pubmed: 21540891doi: 10.1038/nsmb.2066google scholar: lookup
                  20. Komander D. The emerging complexity of protein ubiquitination.. Biochem Soc Trans 2009 Oct;37(Pt 5):937-53.
                    pubmed: 19754430doi: 10.1042/BST0370937google scholar: lookup
                  21. Enesa K, Zakkar M, Chaudhury H, Luong le A, Rawlinson L, Mason JC, Haskard DO, Dean JL, Evans PC. NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling.. J Biol Chem 2008 Mar 14;283(11):7036-45.
                    pubmed: 18178551doi: 10.1074/jbc.M708690200google scholar: lookup
                  22. Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O'Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM. DUBA: a deubiquitinase that regulates type I interferon production.. Science 2007 Dec 7;318(5856):1628-32.
                    pubmed: 17991829doi: 10.1126/science.1145918google scholar: lookup
                  23. Li S, Zheng H, Mao AP, Zhong B, Li Y, Liu Y, Gao Y, Ran Y, Tien P, Shu HB. Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6.. J Biol Chem 2010 Feb 12;285(7):4291-7.
                    pmc: PMC2836033pubmed: 19996094doi: 10.1074/jbc.M109.074971google scholar: lookup
                  24. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.. Nature 2004 Aug 5;430(7000):694-9.
                    pubmed: 15258597doi: 10.1038/nature02794google scholar: lookup
                  25. Jiang X, Chen ZJ. The role of ubiquitylation in immune defence and pathogen evasion.. Nat Rev Immunol 2011 Dec 9;12(1):35-48.
                    pmc: PMC3864900pubmed: 22158412doi: 10.1038/nri3111google scholar: lookup
                  26. Oudshoorn D, Versteeg GA, Kikkert M. Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers.. Cytokine Growth Factor Rev 2012 Dec;23(6):273-82.
                    pmc: PMC7172403pubmed: 22964110doi: 10.1016/j.cytogfr.2012.08.003google scholar: lookup
                  27. Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion.. J Virol 2012 Mar;86(6):2900-10.
                    pmc: PMC3302314pubmed: 22258243doi: 10.1128/JVI.05738-11google scholar: lookup
                  28. O'Neill LA, Bowie AG. Sensing and signaling in antiviral innate immunity.. Curr Biol 2010 Apr 13;20(7):R328-33.
                    pubmed: 20392426doi: 10.1016/j.cub.2010.01.044google scholar: lookup
                  29. Makarova KS, Aravind L, Koonin EV. A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae.. Trends Biochem Sci 2000 Feb;25(2):50-2.
                    pubmed: 10664582doi: 10.1016/s0968-0004(99)01530-3google scholar: lookup
                  30. Sun Z, Chen Z, Lawson SR, Fang Y. The cysteine protease domain of porcine reproductive and respiratory syndrome virus nonstructural protein 2 possesses deubiquitinating and interferon antagonism functions.. J Virol 2010 Aug;84(15):7832-46.
                    pmc: PMC2897636pubmed: 20504922doi: 10.1128/JVI.00217-10google scholar: lookup
                  31. van Kasteren PB, Beugeling C, Ninaber DK, Frias-Staheli N, van Boheemen S, Garcu00eda-Sastre A, Snijder EJ, Kikkert M. Arterivirus and nairovirus ovarian tumor domain-containing Deubiquitinases target activated RIG-I to control innate immune signaling.. J Virol 2012 Jan;86(2):773-85.
                    pmc: PMC3255818pubmed: 22072774doi: 10.1128/JVI.06277-11google scholar: lookup
                  32. Devaraj SG, Wang N, Chen Z, Chen Z, Tseng M, Barretto N, Lin R, Peters CJ, Tseng CT, Baker SC, Li K. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.. J Biol Chem 2007 Nov 2;282(44):32208-21.
                    pmc: PMC2756044pubmed: 17761676doi: 10.1074/jbc.M704870200google scholar: lookup
                  33. Inn KS, Lee SH, Rathbun JY, Wong LY, Toth Z, Machida K, Ou JH, Jung JU. Inhibition of RIG-I-mediated signaling by Kaposi's sarcoma-associated herpesvirus-encoded deubiquitinase ORF64.. J Virol 2011 Oct;85(20):10899-904.
                    pmc: PMC3187500pubmed: 21835791doi: 10.1128/JVI.00690-11google scholar: lookup
                  34. Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling.. J Virol 2009 Jul;83(13):6689-705.
                    pmc: PMC2698564pubmed: 19369340doi: 10.1128/JVI.02220-08google scholar: lookup
                  35. Jiang J, Tang H. Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein.. Protein Cell 2010 Dec;1(12):1106-17.
                    pmc: PMC4875076pubmed: 21213104doi: 10.1007/s13238-010-0141-8google scholar: lookup
                  36. Wang D, Fang L, Li P, Sun L, Fan J, Zhang Q, Luo R, Liu X, Li K, Chen H, Chen Z, Xiao S. The leader proteinase of foot-and-mouth disease virus negatively regulates the type I interferon pathway by acting as a viral deubiquitinase.. J Virol 2011 Apr;85(8):3758-66.
                    pmc: PMC3126127pubmed: 21307201doi: 10.1128/JVI.02589-10google scholar: lookup
                  37. Zheng D, Chen G, Guo B, Cheng G, Tang H. PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production.. Cell Res 2008 Nov;18(11):1105-13.
                    pmc: PMC7091798pubmed: 18957937doi: 10.1038/cr.2008.294google scholar: lookup
                  38. Messick TE, Russell NS, Iwata AJ, Sarachan KL, Shiekhattar R, Shanks JR, Reyes-Turcu FE, Wilkinson KD, Marmorstein R. Structural basis for ubiquitin recognition by the Otu1 ovarian tumor domain protein.. J Biol Chem 2008 Apr 18;283(16):11038-49.
                    pmc: PMC2447653pubmed: 18270205doi: 10.1074/jbc.M704398200google scholar: lookup
                  39. Borodovsky A, Ovaa H, Kolli N, Gan-Erdene T, Wilkinson KD, Ploegh HL, Kessler BM. Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family.. Chem Biol 2002 Oct;9(10):1149-59.
                    pubmed: 12401499doi: 10.1016/s1074-5521(02)00248-xgoogle scholar: lookup
                  40. Andreini C, Bertini I, Cavallaro G. Minimal functional sites allow a classification of zinc sites in proteins.. PLoS One 2011;6(10):e26325.
                    pmc: PMC3197139pubmed: 22043316doi: 10.1371/journal.pone.0026325google scholar: lookup
                  41. Holm L, Rosenstru00f6m P. Dali server: conservation mapping in 3D.. Nucleic Acids Res 2010 Jul;38(Web Server issue):W545-9.
                    pmc: PMC2896194pubmed: 20457744doi: 10.1093/nar/gkq366google scholar: lookup
                  42. Komander D, Clague MJ, Urbu00e9 S. Breaking the chains: structure and function of the deubiquitinases.. Nat Rev Mol Cell Biol 2009 Aug;10(8):550-63.
                    pubmed: 19626045doi: 10.1038/nrm2731google scholar: lookup
                  43. James TW, Frias-Staheli N, Bacik JP, Levingston Macleod JM, Khajehpour M, Garcu00eda-Sastre A, Mark BL. Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease.. Proc Natl Acad Sci U S A 2011 Feb 8;108(6):2222-7.
                    pmc: PMC3038750pubmed: 21245344doi: 10.1073/pnas.1013388108google scholar: lookup
                  44. Akutsu M, Ye Y, Virdee S, Chin JW, Komander D. Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains.. Proc Natl Acad Sci U S A 2011 Feb 8;108(6):2228-33.
                    pmc: PMC3038727pubmed: 21266548doi: 10.1073/pnas.1015287108google scholar: lookup
                  45. Capodagli GC, McKercher MA, Baker EA, Masters EM, Brunzelle JS, Pegan SD. Structural analysis of a viral ovarian tumor domain protease from the Crimean-Congo hemorrhagic fever virus in complex with covalently bonded ubiquitin.. J Virol 2011 Apr;85(7):3621-30.
                    pmc: PMC3067871pubmed: 21228232doi: 10.1128/JVI.02496-10google scholar: lookup
                  46. Juang YC, Landry MC, Sanches M, Vittal V, Leung CC, Ceccarelli DF, Mateo AR, Pruneda JN, Mao DY, Szilard RK, Orlicky S, Munro M, Brzovic PS, Klevit RE, Sicheri F, Durocher D. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function.. Mol Cell 2012 Feb 10;45(3):384-97.
                    pmc: PMC3306812pubmed: 22325355doi: 10.1016/j.molcel.2012.01.011google scholar: lookup
                  47. Wiener R, Zhang X, Wang T, Wolberger C. The mechanism of OTUB1-mediated inhibition of ubiquitination.. Nature 2012 Feb 22;483(7391):618-22.
                    pmc: PMC3319311pubmed: 22367539doi: 10.1038/nature10911google scholar: lookup
                  48. Huang OW, Ma X, Yin J, Flinders J, Maurer T, Kayagaki N, Phung Q, Bosanac I, Arnott D, Dixit VM, Hymowitz SG, Starovasnik MA, Cochran AG. Phosphorylation-dependent activity of the deubiquitinase DUBA.. Nat Struct Mol Biol 2012 Jan 15;19(2):171-5.
                    pubmed: 22245969doi: 10.1038/nsmb.2206google scholar: lookup
                  49. Sun Z, Li Y, Ransburgh R, Snijder EJ, Fang Y. Nonstructural protein 2 of porcine reproductive and respiratory syndrome virus inhibits the antiviral function of interferon-stimulated gene 15.. J Virol 2012 Apr;86(7):3839-50.
                    pmc: PMC3302520pubmed: 22258253doi: 10.1128/JVI.06466-11google scholar: lookup
                  50. Durfee LA, Lyon N, Seo K, Huibregtse JM. The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15.. Mol Cell 2010 Jun 11;38(5):722-32.
                    pmc: PMC2887317pubmed: 20542004doi: 10.1016/j.molcel.2010.05.002google scholar: lookup
                  51. Dikic I, Wakatsuki S, Walters KJ. Ubiquitin-binding domains - from structures to functions.. Nat Rev Mol Cell Biol 2009 Oct;10(10):659-71.
                    pmc: PMC7359374pubmed: 19773779doi: 10.1038/nrm2767google scholar: lookup
                  52. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.. Nature 2007 Apr 19;446(7138):916-920.
                    pubmed: 17392790doi: 10.1038/nature05732google scholar: lookup
                  53. Morrison JM, Racaniello VR. Proteinase 2Apro is essential for enterovirus replication in type I interferon-treated cells.. J Virol 2009 May;83(9):4412-22.
                    pmc: PMC2668472pubmed: 19211759doi: 10.1128/JVI.02177-08google scholar: lookup
                  54. Ventoso I, Carrasco L. A poliovirus 2A(pro) mutant unable to cleave 3CD shows inefficient viral protein synthesis and transactivation defects.. J Virol 1995 Oct;69(10):6280-8.
                    pmc: PMC189526pubmed: 7666528doi: 10.1128/JVI.69.10.6280-6288.1995google scholar: lookup
                  55. Yu SF, Lloyd RE. Identification of essential amino acid residues in the functional activity of poliovirus 2A protease.. Virology 1991 Jun;182(2):615-25.
                    pubmed: 1850921doi: 10.1016/0042-6822(91)90602-8google scholar: lookup
                  56. Yu SF, Benton P, Bovee M, Sessions J, Lloyd RE. Defective RNA replication by poliovirus mutants deficient in 2A protease cleavage activity.. J Virol 1995 Jan;69(1):247-52.
                    pmc: PMC188570pubmed: 7983716doi: 10.1128/JVI.69.1.247-252.1995google scholar: lookup
                  57. Kamphuis IG, Kalk KH, Swarte MB, Drenth J. Structure of papain refined at 1.65 A resolution.. J Mol Biol 1984 Oct 25;179(2):233-56.
                    pubmed: 6502713doi: 10.1016/0022-2836(84)90467-4google scholar: lookup
                  58. Bergeron E, Albariu00f1o CG, Khristova ML, Nichol ST. Crimean-Congo hemorrhagic fever virus-encoded ovarian tumor protease activity is dispensable for virus RNA polymerase function.. J Virol 2010 Jan;84(1):216-26.
                    pmc: PMC2798392pubmed: 19864393doi: 10.1128/JVI.01859-09google scholar: lookup
                  59. Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, Phu L, Phung Q, Maurer B, Arnott D, Kirkpatrick DS, Dixit VM, Hymowitz SG. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-u03baB signaling.. Mol Cell 2010 Nov 24;40(4):548-57.
                    pubmed: 21095585doi: 10.1016/j.molcel.2010.10.009google scholar: lookup
                  60. Zhang J, Timoney PJ, Shuck KM, Seoul G, Go YY, Lu Z, Powell DG, Meade BJ, Balasuriya UB. Molecular epidemiology and genetic characterization of equine arteritis virus isolates associated with the 2006-2007 multi-state disease occurrence in the USA.. J Gen Virol 2010 Sep;91(Pt 9):2286-301.
                    pubmed: 20444993doi: 10.1099/vir.0.019737-0google scholar: lookup
                  61. Holyoak GR, Balasuriya UB, Broaddus CC, Timoney PJ. Equine viral arteritis: current status and prevention.. Theriogenology 2008 Aug;70(3):403-14.
                    pubmed: 18502495doi: 10.1016/j.theriogenology.2008.04.020google scholar: lookup
                  62. Neumann EJ, Kliebenstein JB, Johnson CD, Mabry JW, Bush EJ, Seitzinger AH, Green AL, Zimmerman JJ. Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States.. J Am Vet Med Assoc 2005 Aug 1;227(3):385-92.
                    pubmed: 16121604doi: 10.2460/javma.2005.227.385google scholar: lookup
                  63. Tong GZ, Zhou YJ, Hao XF, Tian ZJ, An TQ, Qiu HJ. Highly pathogenic porcine reproductive and respiratory syndrome, China.. Emerg Infect Dis 2007 Sep;13(9):1434-6.
                    pmc: PMC2857295pubmed: 18252136doi: 10.3201/eid1309.070399google scholar: lookup
                  64. Li Y, Wang X, Bo K, Wang X, Tang B, Yang B, Jiang W, Jiang P. Emergence of a highly pathogenic porcine reproductive and respiratory syndrome virus in the Mid-Eastern region of China.. Vet J 2007 Nov;174(3):577-84.
                    pubmed: 17869553doi: 10.1016/j.tvjl.2007.07.032google scholar: lookup
                  65. Tian K, Yu X, Zhao T, Feng Y, Cao Z, Wang C, Hu Y, Chen X, Hu D, Tian X, Liu D, Zhang S, Deng X, Ding Y, Yang L, Zhang Y, Xiao H, Qiao M, Wang B, Hou L, Wang X, Yang X, Kang L, Sun M, Jin P, Wang S, Kitamura Y, Yan J, Gao GF. Emergence of fatal PRRSV variants: unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark.. PLoS One 2007 Jun 13;2(6):e526.
                    pmc: PMC1885284pubmed: 17565379doi: 10.1371/journal.pone.0000526google scholar: lookup
                  66. Kimman TG, Cornelissen LA, Moormann RJ, Rebel JM, Stockhofe-Zurwieden N. Challenges for porcine reproductive and respiratory syndrome virus (PRRSV) vaccinology.. Vaccine 2009 Jun 8;27(28):3704-18.
                    pubmed: 19464553doi: 10.1016/j.vaccine.2009.04.022google scholar: lookup
                  67. Chen Z, Lawson S, Sun Z, Zhou X, Guan X, Christopher-Hennings J, Nelson EA, Fang Y. Identification of two auto-cleavage products of nonstructural protein 1 (nsp1) in porcine reproductive and respiratory syndrome virus infected cells: nsp1 function as interferon antagonist.. Virology 2010 Mar 1;398(1):87-97.
                    pmc: PMC7111964pubmed: 20006994doi: 10.1016/j.virol.2009.11.033google scholar: lookup
                  68. Beura LK, Sarkar SN, Kwon B, Subramaniam S, Jones C, Pattnaik AK, Osorio FA. Porcine reproductive and respiratory syndrome virus nonstructural protein 1beta modulates host innate immune response by antagonizing IRF3 activation.. J Virol 2010 Feb;84(3):1574-84.
                    pmc: PMC2812326pubmed: 19923190doi: 10.1128/JVI.01326-09google scholar: lookup
                  69. Richt JA, Garcu00eda-Sastre A. Attenuated influenza virus vaccines with modified NS1 proteins.. Curr Top Microbiol Immunol 2009;333:177-95.
                    pubmed: 19768406doi: 10.1007/978-3-540-92165-3_9google scholar: lookup
                  70. Perlman S, Netland J. Coronaviruses post-SARS: update on replication and pathogenesis.. Nat Rev Microbiol 2009 Jun;7(6):439-50.
                    pmc: PMC2830095pubmed: 19430490doi: 10.1038/nrmicro2147google scholar: lookup
                  71. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.. N Engl J Med 2012 Nov 8;367(19):1814-20.
                    pubmed: 23075143doi: 10.1056/NEJMoa1211721google scholar: lookup
                  72. van Boheemen S, et al. 2012. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. mBio 3(6)
                  73. Clementz MA, Chen Z, Banach BS, Wang Y, Sun L, Ratia K, Baez-Santos YM, Wang J, Takayama J, Ghosh AK, Li K, Mesecar AD, Baker SC. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases.. J Virol 2010 May;84(9):4619-29.
                    pmc: PMC2863753pubmed: 20181693doi: 10.1128/JVI.02406-09google scholar: lookup
                  74. Wojdyla JA, Manolaridis I, van Kasteren PB, Kikkert M, Snijder EJ, Gorbalenya AE, Tucker PA. Papain-like protease 1 from transmissible gastroenteritis virus: crystal structure and enzymatic activity toward viral and cellular substrates.. J Virol 2010 Oct;84(19):10063-73.
                    pmc: PMC2937765pubmed: 20668092doi: 10.1128/JVI.00898-10google scholar: lookup
                  75. Ratia K, Saikatendu KS, Santarsiero BD, Barretto N, Baker SC, Stevens RC, Mesecar AD. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme.. Proc Natl Acad Sci U S A 2006 Apr 11;103(15):5717-22.
                    pmc: PMC1458639pubmed: 16581910doi: 10.1073/pnas.0510851103google scholar: lookup
                  76. Gohara DW, Ha CS, Kumar S, Ghosh B, Arnold JJ, Wisniewski TJ, Cameron CE. Production of "authentic" poliovirus RNA-dependent RNA polymerase (3D(pol)) by ubiquitin-protease-mediated cleavage in Escherichia coli.. Protein Expr Purif 1999 Oct;17(1):128-38.
                    pubmed: 10497078doi: 10.1006/prep.1999.1100google scholar: lookup
                  77. . The CCP4 suite: programs for protein crystallography.. Acta Crystallogr D Biol Crystallogr 1994 Sep 1;50(Pt 5):760-3.
                    pubmed: 15299374doi: 10.1107/S0907444994003112google scholar: lookup
                  78. Adams PD, Afonine PV, Bunku00f3czi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH. PHENIX: a comprehensive Python-based system for macromolecular structure solution.. Acta Crystallogr D Biol Crystallogr 2010 Feb;66(Pt 2):213-21.
                    pmc: PMC2815670pubmed: 20124702doi: 10.1107/S0907444909052925google scholar: lookup
                  79. Bru00fcnger AT. Free R value: a novel statistical quantity for assessing the accuracy of crystal structures.. Nature 1992 Jan 30;355(6359):472-5.
                    pubmed: 18481394doi: 10.1038/355472a0google scholar: lookup
                  80. Emsley P, Cowtan K. 2004. Coot: Model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60(Pt 12 Pt 1):2126u20132132.
                  81. van Dinten LC, den Boon JA, Wassenaar AL, Spaan WJ, Snijder EJ. An infectious arterivirus cDNA clone: identification of a replicase point mutation that abolishes discontinuous mRNA transcription.. Proc Natl Acad Sci U S A 1997 Feb 4;94(3):991-6.
                    pmc: PMC19627pubmed: 9023370doi: 10.1073/pnas.94.3.991google scholar: lookup
                  82. Nedialkova DD, Gorbalenya AE, Snijder EJ. Arterivirus Nsp1 modulates the accumulation of minus-strand templates to control the relative abundance of viral mRNAs.. PLoS Pathog 2010 Feb 19;6(2):e1000772.
                    pmc: PMC2824749pubmed: 20174607doi: 10.1371/journal.ppat.1000772google scholar: lookup
                  83. Rozen S, Skaletsky HJ. 2000. Primer3 on the WWW for general users and for biologist programmers. Bioinformatics Methods and Protocols: Methods in Molecular Biology, eds Krawetz S, Misener S (Humana Press, Totowa, NJ), pp 365u2013386.
                  84. DeLano WL. The PyMOL Molecular Graphics System. Palo Alto, CA: DeLano Scientific; 2002.

                  Citations

                  This article has been cited 87 times.
                  1. Ozhelvaci F, Steczkiewicz K. Identification and classification of papain-like cysteine proteinases.. J Biol Chem 2023 Jun;299(6):104801.
                    doi: 10.1016/j.jbc.2023.104801pubmed: 37164157google scholar: lookup
                  2. Su CM, Du Y, Rowland RRR, Wang Q, Yoo D. Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses.. Front Immunol 2023;14:1172000.
                    doi: 10.3389/fimmu.2023.1172000pubmed: 37138878google scholar: lookup
                  3. Myeni SK, Bredenbeek PJ, Knaap RCM, Dalebout TJ, Morales ST, Sidorov IA, Linger ME, Oreshkova N, van Zanen-Gerhardt S, Zander SAL, Enjuanes L, Sola I, Snijder EJ, Kikkert M. Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase.. Nat Commun 2023 Feb 28;14(1):1141.
                    doi: 10.1038/s41467-023-36754-zpubmed: 36854765google scholar: lookup
                  4. Treffers EE, Tas A, Scholte FEM, de Ru AH, Snijder EJ, van Veelen PA, van Hemert MJ. The alphavirus nonstructural protein 2 NTPase induces a host translational shut-off through phosphorylation of eEF2 via cAMP-PKA-eEF2K signaling.. PLoS Pathog 2023 Feb;19(2):e1011179.
                    doi: 10.1371/journal.ppat.1011179pubmed: 36848386google scholar: lookup
                  5. Jian Z, Ma R, Zhu L, Deng H, Li F, Zhao J, Deng L, Lai S, Sun X, Tang H, Xu Z. Evasion of interferon-mediated immune response by arteriviruses.. Front Immunol 2022;13:963923.
                    doi: 10.3389/fimmu.2022.963923pubmed: 36091073google scholar: lookup
                  6. Ran XH, Zhu JW, Chen YY, Ni RZ, Mu D. Papain-like protease of SARS-CoV-2 inhibits RLR signaling in a deubiquitination-dependent and deubiquitination-independent manner.. Front Immunol 2022;13:947272.
                    doi: 10.3389/fimmu.2022.947272pubmed: 36032116google scholar: lookup
                  7. Zhang Q, Jia Q, Gao W, Zhang W. The Role of Deubiquitinases in Virus Replication and Host Innate Immune Response.. Front Microbiol 2022;13:839624.
                    doi: 10.3389/fmicb.2022.839624pubmed: 35283827google scholar: lookup
                  8. van Gent M, Chiang JJ, Muppala S, Chiang C, Azab W, Kattenhorn L, Knipe DM, Osterrieder N, Gack MU. The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.. J Virol 2022 Feb 23;96(4):e0151021.
                    doi: 10.1128/JVI.01510-21pubmed: 34935440google scholar: lookup
                  9. Zhou Z, Xu J, Li Z, Lv Y, Wu S, Zhang H, Song Y, Ai Y. Viral deubiquitinases and innate antiviral immune response in livestock and poultry.. J Vet Med Sci 2022 Jan 13;84(1):102-113.
                    doi: 10.1292/jvms.21-0199pubmed: 34803084google scholar: lookup
                  10. Singh P, Chauhan SS, Pandit S, Sinha M, Gupta S, Gupta A, Parthasarathi R. The dual role of phytochemicals on SARS-CoV-2 inhibition by targeting host and viral proteins.. J Tradit Complement Med 2022 Jan;12(1):90-99.
                    doi: 10.1016/j.jtcme.2021.09.001pubmed: 34513611google scholar: lookup
                  11. Atkins JF, O'Connor KM, Bhatt PR, Loughran G. From Recoding to Peptides for MHC Class I Immune Display: Enriching Viral Expression, Virus Vulnerability and Virus Evasion.. Viruses 2021 Jun 27;13(7).
                    doi: 10.3390/v13071251pubmed: 34199077google scholar: lookup
                  12. Sivakumar D, Stein M. Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases.. Biomolecules 2021 May 28;11(6).
                    doi: 10.3390/biom11060802pubmed: 34071582google scholar: lookup
                  13. Proulx J, Borgmann K, Park IW. Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle.. Int J Mol Sci 2021 Apr 23;22(9).
                    doi: 10.3390/ijms22094438pubmed: 33922750google scholar: lookup
                  14. Ma J, Ma L, Yang M, Wu W, Feng W, Chen Z. The Function of the PRRSV-Host Interactions and Their Effects on Viral Replication and Propagation in Antiviral Strategies.. Vaccines (Basel) 2021 Apr 9;9(4).
                    doi: 10.3390/vaccines9040364pubmed: 33918746google scholar: lookup
                  15. Guo R, Yan X, Li Y, Cui J, Misra S, Firth AE, Snijder EJ, Fang Y. A swine arterivirus deubiquitinase stabilizes two major envelope proteins and promotes production of viral progeny.. PLoS Pathog 2021 Mar;17(3):e1009403.
                    doi: 10.1371/journal.ppat.1009403pubmed: 33735221google scholar: lookup
                  16. Song K, Li S. The Role of Ubiquitination in NF-u03baB Signaling during Virus Infection.. Viruses 2021 Jan 20;13(2).
                    doi: 10.3390/v13020145pubmed: 33498196google scholar: lookup
                  17. Zolfaghari Emameh R, Eftekhari M, Nosrati H, Heshmatnia J, Falak R. Identification and characterization of a silent mutation in RNA binding domain of N protein coding gene from SARS-CoV-2.. BMC Res Notes 2021 Jan 6;14(1):10.
                    doi: 10.1186/s13104-020-05439-xpubmed: 33407800google scholar: lookup
                  18. Yan S, Wu G. Spatial and temporal roles of SARS-CoV PL(pro) -A snapshot.. FASEB J 2021 Jan;35(1):e21197.
                    doi: 10.1096/fj.202002271pubmed: 33368679google scholar: lookup
                  19. Li M, Ye G, Si Y, Shen Z, Liu Z, Shi Y, Xiao S, Fu ZF, Peng G. Structure of the multiple functional domains from coronavirus nonstructural protein 3.. Emerg Microbes Infect 2021 Dec;10(1):66-80.
                    doi: 10.1080/22221751.2020.1865840pubmed: 33327866google scholar: lookup
                  20. Shin D, Bhattacharya A, Cheng YL, Alonso MC, Mehdipour AR, van der Heden van Noort GJ, Ovaa H, Hummer G, Dikic I. Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection.. Elife 2020 Nov 13;9.
                    doi: 10.7554/eLife.58277pubmed: 33185526google scholar: lookup
                  21. Denessiouk K, Uversky VN, Permyakov SE, Permyakov EA, Johnson MS, Denesyuk AI. Papain-like cysteine proteinase zone (PCP-zone) and PCP structural catalytic core (PCP-SCC) of enzymes with cysteine proteinase fold.. Int J Biol Macromol 2020 Dec 15;165(Pt A):1438-1446.
                    doi: 10.1016/j.ijbiomac.2020.10.022pubmed: 33058970google scholar: lookup
                  22. Devignot S, Kromer T, Mirazimi A, Weber F. ISG15 overexpression compensates the defect of Crimean-Congo hemorrhagic fever virus polymerase bearing a protease-inactive ovarian tumor domain.. PLoS Negl Trop Dis 2020 Sep;14(9):e0008610.
                    doi: 10.1371/journal.pntd.0008610pubmed: 32931521google scholar: lookup
                  23. Fieulaine S, Witte MD, Theile CS, Ayach M, Ploegh HL, Jupin I, Bressanelli S. Turnip yellow mosaic virus protease binds ubiquitin suboptimally to fine-tune its deubiquitinase activity.. J Biol Chem 2020 Oct 2;295(40):13769-13783.
                    doi: 10.1074/jbc.RA120.014628pubmed: 32732284google scholar: lookup
                  24. Visser LJ, Aloise C, Swatek KN, Medina GN, Olek KM, Rabouw HH, de Groot RJ, Langereis MA, de Los Santos T, Komander D, Skern T, van Kuppeveld FJM. Dissecting distinct proteolytic activities of FMDV Lpro implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression.. PLoS Pathog 2020 Jul;16(7):e1008702.
                    doi: 10.1371/journal.ppat.1008702pubmed: 32667958google scholar: lookup
                  25. Schubert AF, Nguyen JV, Franklin TG, Geurink PP, Roberts CG, Sanderson DJ, Miller LN, Ovaa H, Hofmann K, Pruneda JN, Komander D. Identification and characterization of diverse OTU deubiquitinases in bacteria.. EMBO J 2020 Aug 3;39(15):e105127.
                    doi: 10.15252/embj.2020105127pubmed: 32567101google scholar: lookup
                  26. Tchesnokov EP, Bailey-Elkin BA, Mark BL, Gu00f6tte M. Independent inhibition of the polymerase and deubiquitinase activities of the Crimean-Congo Hemorrhagic Fever Virus full-length L-protein.. PLoS Negl Trop Dis 2020 Jun;14(6):e0008283.
                    doi: 10.1371/journal.pntd.0008283pubmed: 32497085google scholar: lookup
                  27. Freitas BT, Durie IA, Murray J, Longo JE, Miller HC, Crich D, Hogan RJ, Tripp RA, Pegan SD. Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease.. ACS Infect Dis 2020 Aug 14;6(8):2099-2109.
                    doi: 10.1021/acsinfecdis.0c00168pubmed: 32428392google scholar: lookup
                  28. Clasman JR, Everett RK, Srinivasan K, Mesecar AD. Decoupling deISGylating and deubiquitinating activities of the MERS virus papain-like protease.. Antiviral Res 2020 Feb;174:104661.
                    doi: 10.1016/j.antiviral.2019.104661pubmed: 31765674google scholar: lookup
                  29. Zhou S, Ge X, Kong C, Liu T, Liu A, Gao P, Song J, Zhou L, Guo X, Han J, Yang H. Characterizing the PRRSV nsp2 Deubiquitinase Reveals Dispensability of Cis-Activity for Replication and a Link of nsp2 to Inflammation Induction.. Viruses 2019 Sep 26;11(10).
                    doi: 10.3390/v11100896pubmed: 31561412google scholar: lookup
                  30. Yang L, He J, Wang R, Zhang X, Lin S, Ma Z, Zhang Y. Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Induces STAT2 Degradation To Inhibit Interferon Signaling.. J Virol 2019 Nov 15;93(22).
                    doi: 10.1128/JVI.01352-19pubmed: 31462568google scholar: lookup
                  31. Majzoub K, Wrensch F, Baumert TF. The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans.. Viruses 2019 Aug 16;11(8).
                    doi: 10.3390/v11080758pubmed: 31426357google scholar: lookup
                  32. de Wilde AH, Boomaars-van der Zanden AL, de Jong AWM, Bu00e1rcena M, Snijder EJ, Posthuma CC. Adaptive Mutations in Replicase Transmembrane Subunits Can Counteract Inhibition of Equine Arteritis Virus RNA Synthesis by Cyclophilin Inhibitors.. J Virol 2019 Sep 15;93(18).
                    doi: 10.1128/JVI.00490-19pubmed: 31243130google scholar: lookup
                  33. Woo B, Baek KH. Regulatory interplay between deubiquitinating enzymes and cytokines.. Cytokine Growth Factor Rev 2019 Aug;48:40-51.
                    doi: 10.1016/j.cytogfr.2019.06.001pubmed: 31208841google scholar: lookup
                  34. Li Y, Firth AE, Brierley I, Cai Y, Napthine S, Wang T, Yan X, Kuhn JH, Fang Y. Programmed -2/-1 Ribosomal Frameshifting in Simarteriviruses: an Evolutionarily Conserved Mechanism.. J Virol 2019 Aug 15;93(16).
                    doi: 10.1128/JVI.00370-19pubmed: 31167906google scholar: lookup
                  35. Dzimianski JV, Scholte FEM, Bergeron u00c9, Pegan SD. ISG15: It's Complicated.. J Mol Biol 2019 Oct 4;431(21):4203-4216.
                    doi: 10.1016/j.jmb.2019.03.013pubmed: 30890331google scholar: lookup
                  36. Mann KS, Sanfau00e7on H. Expanding Repertoire of Plant Positive-Strand RNA Virus Proteases.. Viruses 2019 Jan 15;11(1).
                    doi: 10.3390/v11010066pubmed: 30650571google scholar: lookup
                  37. Niemeyer D, Mu00f6sbauer K, Klein EM, Sieberg A, Mettelman RC, Mielech AM, Dijkman R, Baker SC, Drosten C, Mu00fcller MA. The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species.. PLoS Pathog 2018 Sep;14(9):e1007296.
                    doi: 10.1371/journal.ppat.1007296pubmed: 30248143google scholar: lookup
                  38. Deng L, Zeng Q, Wang M, Cheng A, Jia R, Chen S, Zhu D, Liu M, Yang Q, Wu Y, Zhao X, Zhang S, Liu Y, Yu Y, Zhang L, Chen X. Suppression of NF-u03baB Activity: A Viral Immune Evasion Mechanism.. Viruses 2018 Aug 4;10(8).
                    doi: 10.3390/v10080409pubmed: 30081579google scholar: lookup
                  39. Tang Q, Wu P, Chen H, Li G. Pleiotropic roles of the ubiquitin-proteasome system during viral propagation.. Life Sci 2018 Aug 15;207:350-354.
                    doi: 10.1016/j.lfs.2018.06.014pubmed: 29913185google scholar: lookup
                  40. Rodamilans B, Shan H, Pasin F, Garcu00eda JA. Plant Viral Proteases: Beyond the Role of Peptide Cutters.. Front Plant Sci 2018;9:666.
                    doi: 10.3389/fpls.2018.00666pubmed: 29868107google scholar: lookup
                  41. Bester SM, Daczkowski CM, Faaberg KS, Pegan SD. Insights into the Porcine Reproductive and Respiratory Syndrome Virus Viral Ovarian Tumor Domain Protease Specificity for Ubiquitin and Interferon Stimulated Gene Product 15.. ACS Infect Dis 2018 Sep 14;4(9):1316-1326.
                    doi: 10.1021/acsinfecdis.8b00068pubmed: 29856201google scholar: lookup
                  42. Jupin I, Ayach M, Jomat L, Fieulaine S, Bressanelli S. A mobile loop near the active site acts as a switch between the dual activities of a viral protease/deubiquitinase.. PLoS Pathog 2017 Nov;13(11):e1006714.
                    doi: 10.1371/journal.ppat.1006714pubmed: 29117247google scholar: lookup
                  43. Scholte FEM, Zivcec M, Dzimianski JV, Deaton MK, Spengler JR, Welch SR, Nichol ST, Pegan SD, Spiropoulou CF, Bergeron u00c9. Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease.. Cell Rep 2017 Sep 5;20(10):2396-2407.
                    doi: 10.1016/j.celrep.2017.08.040pubmed: 28877473google scholar: lookup
                  44. Scutigliani EM, Kikkert M. Interaction of the innate immune system with positive-strand RNA virus replication organelles.. Cytokine Growth Factor Rev 2017 Oct;37:17-27.
                    doi: 10.1016/j.cytogfr.2017.05.007pubmed: 28709747google scholar: lookup
                  45. Wen X, Bian T, Zhang Z, Zhou L, Ge X, Han J, Guo X, Yang H, Yu K. Interleukin-2 enhancer binding factor 2 interacts with the nsp9 or nsp2 of porcine reproductive and respiratory syndrome virus and exerts negatively regulatory effect on the viral replication.. Virol J 2017 Jul 11;14(1):125.
                    doi: 10.1186/s12985-017-0794-5pubmed: 28693575google scholar: lookup
                  46. Dowall SD, Carroll MW, Hewson R. Development of vaccines against Crimean-Congo haemorrhagic fever virus.. Vaccine 2017 Oct 20;35(44):6015-6023.
                    doi: 10.1016/j.vaccine.2017.05.031pubmed: 28687403google scholar: lookup
                  47. de Wilde AH, Snijder EJ, Kikkert M, van Hemert MJ. Host Factors in Coronavirus Replication.. Curr Top Microbiol Immunol 2018;419:1-42.
                    doi: 10.1007/82_2017_25pubmed: 28643204google scholar: lookup
                  48. Bailey-Elkin BA, Knaap RCM, Kikkert M, Mark BL. Structure and Function of Viral Deubiquitinating Enzymes.. J Mol Biol 2017 Nov 10;429(22):3441-3470.
                    doi: 10.1016/j.jmb.2017.06.010pubmed: 28625850google scholar: lookup
                  49. Zhang W, Bailey-Elkin BA, Knaap RCM, Khare B, Dalebout TJ, Johnson GG, van Kasteren PB, McLeish NJ, Gu J, He W, Kikkert M, Mark BL, Sidhu SS. Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants.. PLoS Pathog 2017 May;13(5):e1006372.
                    doi: 10.1371/journal.ppat.1006372pubmed: 28542609google scholar: lookup
                  50. Shang P, Misra S, Hause B, Fang Y. A Naturally Occurring Recombinant Enterovirus Expresses a Torovirus Deubiquitinase.. J Virol 2017 Jul 15;91(14).
                    doi: 10.1128/JVI.00450-17pubmed: 28490584google scholar: lookup
                  51. Clasman JR, Bu00e1ez-Santos YM, Mettelman RC, O'Brien A, Baker SC, Mesecar AD. X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design.. Sci Rep 2017 Jan 12;7:40292.
                    doi: 10.1038/srep40292pubmed: 28079137google scholar: lookup
                  52. Gulyaeva A, Dunowska M, Hoogendoorn E, Giles J, Samborskiy D, Gorbalenya AE. Domain Organization and Evolution of the Highly Divergent 5' Coding Region of Genomes of Arteriviruses, Including the Novel Possum Nidovirus.. J Virol 2017 Mar 15;91(6).
                    doi: 10.1128/JVI.02096-16pubmed: 28053107google scholar: lookup
                  53. Oudshoorn D, van der Hoeven B, Limpens RW, Beugeling C, Snijder EJ, Bu00e1rcena M, Kikkert M. Antiviral Innate Immune Response Interferes with the Formation of Replication-Associated Membrane Structures Induced by a Positive-Strand RNA Virus.. mBio 2016 Dec 6;7(6).
                    doi: 10.1128/mBio.01991-16pubmed: 27923923google scholar: lookup
                  54. Neuman BW. Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles.. Antiviral Res 2016 Nov;135:97-107.
                    doi: 10.1016/j.antiviral.2016.10.005pubmed: 27743916google scholar: lookup
                  55. Nan Y, Zhang YJ. Molecular Biology and Infection of Hepatitis E Virus.. Front Microbiol 2016;7:1419.
                    doi: 10.3389/fmicb.2016.01419pubmed: 27656178google scholar: lookup
                  56. Chan YK, Gack MU. Viral evasion of intracellular DNA and RNA sensing.. Nat Rev Microbiol 2016 Jun;14(6):360-73.
                    doi: 10.1038/nrmicro.2016.45pubmed: 27174148google scholar: lookup
                  57. Ronau JA, Beckmann JF, Hochstrasser M. Substrate specificity of the ubiquitin and Ubl proteases.. Cell Res 2016 Apr;26(4):441-56.
                    doi: 10.1038/cr.2016.38pubmed: 27012468google scholar: lookup
                  58. Li Y, Shyu DL, Shang P, Bai J, Ouyang K, Dhakal S, Hiremath J, Binjawadagi B, Renukaradhya GJ, Fang Y. Mutations in a Highly Conserved Motif of nsp1u03b2 Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus.. J Virol 2016 Jan 20;90(7):3584-99.
                    doi: 10.1128/JVI.03069-15pubmed: 26792733google scholar: lookup
                  59. Chen Y, Savinov SN, Mielech AM, Cao T, Baker SC, Mesecar AD. X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions.. J Biol Chem 2015 Oct 16;290(42):25293-306.
                    doi: 10.1074/jbc.M115.662130pubmed: 26296883google scholar: lookup
                  60. van Kasteren PB, Knaap RC, van den Elzen P, Snijder EJ, Balasuriya UB, van den Born E, Kikkert M. In vivo assessment of equine arteritis virus vaccine improvement by disabling the deubiquitinase activity of papain-like protease 2.. Vet Microbiol 2015 Jul 9;178(1-2):132-7.
                    doi: 10.1016/j.vetmic.2015.04.018pubmed: 25975520google scholar: lookup
                  61. Mielech AM, Deng X, Chen Y, Kindler E, Wheeler DL, Mesecar AD, Thiel V, Perlman S, Baker SC. Murine coronavirus ubiquitin-like domain is important for papain-like protease stability and viral pathogenesis.. J Virol 2015 May;89(9):4907-17.
                    doi: 10.1128/JVI.00338-15pubmed: 25694594google scholar: lookup
                  62. Chan YK, Gack MU. RIG-I-like receptor regulation in virus infection and immunity.. Curr Opin Virol 2015 Jun;12:7-14.
                    doi: 10.1016/j.coviro.2015.01.004pubmed: 25644461google scholar: lookup
                  63. V'kovski P, Al-Mulla H, Thiel V, Neuman BW. New insights on the role of paired membrane structures in coronavirus replication.. Virus Res 2015 Apr 16;202:33-40.
                    doi: 10.1016/j.virusres.2014.12.021pubmed: 25550072google scholar: lookup
                  64. Steinbach F, Westcott DG, McGowan SL, Grierson SS, Frossard JP, Choudhury B. Re-emergence of a genetic outlier strain of equine arteritis virus: Impact on phylogeny.. Virus Res 2015 Apr 16;202:144-50.
                    doi: 10.1016/j.virusres.2014.12.009pubmed: 25527462google scholar: lookup
                  65. Nan Y, Nan G, Zhang YJ. Interferon induction by RNA viruses and antagonism by viral pathogens.. Viruses 2014 Dec 12;6(12):4999-5027.
                    doi: 10.3390/v6124999pubmed: 25514371google scholar: lookup
                  66. Nolte MA, van der Meer JW. Inflammatory responses to infection: the Dutch contribution.. Immunol Lett 2014 Dec;162(2 Pt B):113-20.
                    doi: 10.1016/j.imlet.2014.10.007pubmed: 25455597google scholar: lookup
                  67. Brinton MA, Di H, Vatter HA. Simian hemorrhagic fever virus: Recent advances.. Virus Res 2015 Apr 16;202:112-9.
                    doi: 10.1016/j.virusres.2014.11.024pubmed: 25455336google scholar: lookup
                  68. Bailey-Elkin BA, Knaap RC, Johnson GG, Dalebout TJ, Ninaber DK, van Kasteren PB, Bredenbeek PJ, Snijder EJ, Kikkert M, Mark BL. Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression.. J Biol Chem 2014 Dec 12;289(50):34667-82.
                    doi: 10.1074/jbc.M114.609644pubmed: 25320088google scholar: lookup
                  69. Han M, Yoo D. Modulation of innate immune signaling by nonstructural protein 1 (nsp1) in the family Arteriviridae.. Virus Res 2014 Dec 19;194:100-9.
                    doi: 10.1016/j.virusres.2014.09.007pubmed: 25262851google scholar: lookup
                  70. Bu00e1ez-Santos YM, Mielech AM, Deng X, Baker S, Mesecar AD. Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus.. J Virol 2014 Nov;88(21):12511-27.
                    doi: 10.1128/JVI.01294-14pubmed: 25142582google scholar: lookup
                  71. Nan Y, Yu Y, Ma Z, Khattar SK, Fredericksen B, Zhang YJ. Hepatitis E virus inhibits type I interferon induction by ORF1 products.. J Virol 2014 Oct;88(20):11924-32.
                    doi: 10.1128/JVI.01935-14pubmed: 25100852google scholar: lookup
                  72. Go YY, Li Y, Chen Z, Han M, Yoo D, Fang Y, Balasuriya UB. Equine arteritis virus does not induce interferon production in equine endothelial cells: identification of nonstructural protein 1 as a main interferon antagonist.. Biomed Res Int 2014;2014:420658.
                    doi: 10.1155/2014/420658pubmed: 24967365google scholar: lookup
                  73. Wang L, Zhou L, Zhang H, Li Y, Ge X, Guo X, Yu K, Yang H. Interactome profile of the host cellular proteins and the nonstructural protein 2 of porcine reproductive and respiratory syndrome virus.. PLoS One 2014;9(6):e99176.
                    doi: 10.1371/journal.pone.0099176pubmed: 24901321google scholar: lookup
                  74. Vatter HA, Di H, Donaldson EF, Radu GU, Maines TR, Brinton MA. Functional analyses of the three simian hemorrhagic fever virus nonstructural protein 1 papain-like proteases.. J Virol 2014 Aug;88(16):9129-40.
                    doi: 10.1128/JVI.01020-14pubmed: 24899184google scholar: lookup
                  75. Ratia K, Kilianski A, Baez-Santos YM, Baker SC, Mesecar A. Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating activity of SARS-CoV papain-like protease.. PLoS Pathog 2014 May;10(5):e1004113.
                    doi: 10.1371/journal.ppat.1004113pubmed: 24854014google scholar: lookup
                  76. Li Y, Treffers EE, Napthine S, Tas A, Zhu L, Sun Z, Bell S, Mark BL, van Veelen PA, van Hemert MJ, Firth AE, Brierley I, Snijder EJ, Fang Y. Transactivation of programmed ribosomal frameshifting by a viral protein.. Proc Natl Acad Sci U S A 2014 May 27;111(21):E2172-81.
                    doi: 10.1073/pnas.1321930111pubmed: 24825891google scholar: lookup
                  77. Deaton MK, Spear A, Faaberg KS, Pegan SD. The vOTU domain of highly-pathogenic porcine reproductive and respiratory syndrome virus displays a differential substrate preference.. Virology 2014 Apr;454-455:247-53.
                    doi: 10.1016/j.virol.2014.02.026pubmed: 24725951google scholar: lookup
                  78. Bailey-Elkin BA, van Kasteren PB, Snijder EJ, Kikkert M, Mark BL. Viral OTU deubiquitinases: a structural and functional comparison.. PLoS Pathog 2014 Mar;10(3):e1003894.
                    doi: 10.1371/journal.ppat.1003894pubmed: 24676359google scholar: lookup
                  79. Chen X, Yang X, Zheng Y, Yang Y, Xing Y, Chen Z. SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.. Protein Cell 2014 May;5(5):369-81.
                    doi: 10.1007/s13238-014-0026-3pubmed: 24622840google scholar: lookup
                  80. van Gent M, Braem SG, de Jong A, Delagic N, Peeters JG, Boer IG, Moynagh PN, Kremmer E, Wiertz EJ, Ovaa H, Griffin BD, Ressing ME. Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling.. PLoS Pathog 2014 Feb;10(2):e1003960.
                    doi: 10.1371/journal.ppat.1003960pubmed: 24586164google scholar: lookup
                  81. Mielech AM, Chen Y, Mesecar AD, Baker SC. Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities.. Virus Res 2014 Dec 19;194:184-90.
                    doi: 10.1016/j.virusres.2014.01.025pubmed: 24512893google scholar: lookup
                  82. Mielech AM, Kilianski A, Baez-Santos YM, Mesecar AD, Baker SC. MERS-CoV papain-like protease has deISGylating and deubiquitinating activities.. Virology 2014 Feb;450-451:64-70.
                    doi: 10.1016/j.virol.2013.11.040pubmed: 24503068google scholar: lookup
                  83. Deng Z, Lehmann KC, Li X, Feng C, Wang G, Zhang Q, Qi X, Yu L, Zhang X, Feng W, Wu W, Gong P, Tao Y, Posthuma CC, Snijder EJ, Gorbalenya AE, Chen Z. Structural basis for the regulatory function of a complex zinc-binding domain in a replicative arterivirus helicase resembling a nonsense-mediated mRNA decay helicase.. Nucleic Acids Res 2014 Mar;42(5):3464-77.
                    doi: 10.1093/nar/gkt1310pubmed: 24369429google scholar: lookup
                  84. Wang S, Wang K, Li J, Zheng C. Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3.. J Virol 2013 Nov;87(21):11851-60.
                    doi: 10.1128/JVI.01211-13pubmed: 23986588google scholar: lookup
                  85. Balasuriya UB, Go YY, MacLachlan NJ. Equine arteritis virus.. Vet Microbiol 2013 Nov 29;167(1-2):93-122.
                    doi: 10.1016/j.vetmic.2013.06.015pubmed: 23891306google scholar: lookup
                  86. Rajsbaum R, Garcu00eda-Sastre A. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.. Trends Microbiol 2013 Aug;21(8):421-9.
                    doi: 10.1016/j.tim.2013.06.006pubmed: 23850008google scholar: lookup
                  87. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RWAL, Posthuma CC, van der Meer Y, Bu00e1rcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-u03b1 treatment.. J Gen Virol 2013 Aug;94(Pt 8):1749-1760.
                    doi: 10.1099/vir.0.052910-0pubmed: 23620378google scholar: lookup

                  Secure Payments

                  PayPal Visa Mastercard American Express

                  Satisfaction Guarantee

                  We offer a 60-day guarantee to ensure you are completely satisfied.

                  Fast & Free Shipping

                  We provide fast and free shipping on all orders over $40.

                  Use Nutrition Calculator
                  Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
                  Talk to a Nutritionist
                  Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
                  Submit Diet Evaluation
                  Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists