FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Sci Rep / Interaction of septin 7 and DOCK8 in equine lymphocytes reve...
Scientific reports2018; 8(1); 12332; doi: 10.1038/s41598-018-30753-7

Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity.

Abstract: The GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter- and intracellular signaling in autoimmune disease.
Get Full Text
Publication Date: 2018-08-17 PubMed ID: 30120291PubMed Central: PMC6098150DOI: 10.1038/s41598-018-30753-7Google 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.
LinkedInCopy
  • 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.

The research initially aims to identify the function of the protein septin 7 in lymphocytes, leading to the discovery of DOCK8 as an interaction partner. The study observes notably reduced DOCK8 expression in cases of equine recurrent uveitis (ERU), indicating its potential role in autoimmune mechanisms.

Understanding Septin 7

  • Septin 7 is a GTP-binding protein known to be involved in numerous cellular processes.
  • Such processes include cytoskeleton organization, migration, and the regulation of cell shape.
  • Despite its significant role in various cellular processes, little is known about Septin 7’s functionality in lymphocytes – a type of white blood cell crucial for immune responses.

Link between Septin 7 and Autoimmunity

  • The researchers applied interaction proteomics to explore how Septin 7 works in hematopoietic cells, a type of stem cell that generates blood and immune cells.
  • Prior findings suggested reduced Septin 7 expression in blood-derived lymphocytes found in cases of ERU, a spontaneous animal model for autoimmune uveitis in humans.
  • The researchers suggest that the changes in Septin 7 expression could position it as a key player in the autoimmune process.

Identification of DOCK8 and Its Role

  • In further exploring Septin 7’s functionality, DOCK8 was identified as an interaction partner in primary blood-derived lymphocytes.
  • DOCK8 is associated with crucial immune functions. Thus, the researchers noted a statistically significant decrease in DOCK8 expression in ERU.
  • This suggests that alterations in DOCK8’s interaction network might explain changes in immune response, indicating DOCK8’s role in the pathomechanisms of spontaneous autoimmune diseases.

Uncovering DOCK8 Function and ILK Role

  • Further analyses also shed light on DOCK8’s functions, by identifying the signal transducer integrin-linked kinase (ILK) as a DOCK8 interactor in lymphocytes.
  • The study found an increased presence of ILK (enhanced enrichment) in ERU cases, suggesting that DOCK8 may have a divergent influence on intercellular and intracellular signaling in autoimmune disease.

Cite This Article

APA
Schauer M, Kleinwort KJH, Degroote RL, Wiedemann C, Kremmer E, Hauck SM, Deeg CA. (2018). Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity. Sci Rep, 8(1), 12332. https://doi.org/10.1038/s41598-018-30753-7

Publication

Scientific reports
ISSN: 2045-2322
NlmUniqueID: 101563288
Country: England
Language: English
Volume: 8
Issue: 1
Pages: 12332

Researcher Affiliations

Schauer, Melanie
  • Chair for Animal Physiology, Department of Veterinary Sciences, LMU Munich, 80539, Munich, Germany.
Kleinwort, Kristina J H
  • Chair for Animal Physiology, Department of Veterinary Sciences, LMU Munich, 80539, Munich, Germany.
Degroote, Roxane L
  • Chair for Animal Physiology, Department of Veterinary Sciences, LMU Munich, 80539, Munich, Germany.
Wiedemann, Carmen
  • Chair for Animal Physiology, Department of Veterinary Sciences, LMU Munich, 80539, Munich, Germany.
Kremmer, Elisabeth
  • Institute for Molecular Immunology, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, 81377, Munich, Germany.
Hauck, Stefanie M
  • Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, 80939, Munich, Germany.
Deeg, Cornelia A
  • Chair for Animal Physiology, Department of Veterinary Sciences, LMU Munich, 80539, Munich, Germany. Cornelia.Deeg@lmu.de.

MeSH Terms

  • Animals
  • Apoptosis
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / mortality
  • Autoimmunity
  • Biomarkers
  • Case-Control Studies
  • Cell Cycle Proteins / metabolism
  • Chromatography, Liquid
  • Disease Models, Animal
  • Guanine Nucleotide Exchange Factors / metabolism
  • Horses
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Protein Binding
  • Septins / metabolism
  • Signal Transduction
  • Tandem Mass Spectrometry

Grant Funding

  • DE 719/4 3 / Deutsche Forschungsgemeinschaft (German Research Foundation)

Conflict of Interest Statement

The authors declare no competing interests.

References

This article includes 46 references
  1. Menon MB. Genetic deletion of SEPT7 reveals a cell type-specific role of septins in microtubule destabilization for the completion of cytokinesis.. PLoS Genet 2014;10:e1004558.
    doi: 10.1371/journal.pgen.1004558pmc: PMC4133155pubmed: 25122120google scholar: lookup
  2. Gilden JK, Peck S, Chen YC, Krummel MF. The septin cytoskeleton facilitates membrane retraction during motility and blebbing.. J Cell Biol 2012;196:103–114.
    doi: 10.1083/jcb.201105127pmc: PMC3255977pubmed: 22232702google scholar: lookup
  3. Mostowy S, Cossart P. Septins: the fourth component of the cytoskeleton.. Nat Rev Mol Cell Biol 2012;13:183–194.
    doi: 10.1038/nrm3284pubmed: 22314400google scholar: lookup
  4. Kinoshita M, Field CM, Coughlin ML, Straight AF, Mitchison TJ. Self- and actin-templated assembly of Mammalian septins.. Dev Cell 2002;3:791–802.
    doi: 10.1016/S1534-5807(02)00366-0pubmed: 12479805google scholar: lookup
  5. Kinoshita M. Assembly of mammalian septins.. J Biochem 2003;134:491–496.
    doi: 10.1093/jb/mvg182pubmed: 14607974google scholar: lookup
  6. Sirajuddin M. Structural insight into filament formation by mammalian septins.. Nature 2007;449:311–315.
    doi: 10.1038/nature06052pubmed: 17637674google scholar: lookup
  7. Degroote RL. Unraveling the equine lymphocyte proteome: differential septin 7 expression associates with immune cells in equine recurrent uveitis.. PLoS One 2014;9:e91684.
    doi: 10.1371/journal.pone.0091684pmc: PMC3951111pubmed: 24614191google scholar: lookup
  8. Deeg CA. Equine recurrent uveitis–a spontaneous horse model of uveitis.. Ophthalmic Res 2008;40:151–153.
    doi: 10.1159/000119867pubmed: 18421230google scholar: lookup
  9. Gilger BC. Characterization of T-lymphocytes in the anterior uvea of eyes with chronic equine recurrent uveitis.. Vet Immunol Immunopathol 1999;71:17–28.
    doi: 10.1016/S0165-2427(99)00082-3pubmed: 10522783google scholar: lookup
  10. Deeg CA. Uveitis in horses induced by interphotoreceptor retinoid-binding protein is similar to the spontaneous disease.. Eur J Immunol 2002;32:2598–2606.
    doi: 10.1002/1521-4141(200209)32:9<2598::AID-IMMU2598>3.0.CO;2-#pubmed: 12207344google scholar: lookup
  11. Tooley AJ. Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.. Nat Cell Biol 2009;11:17–26.
    doi: 10.1038/ncb1808pmc: PMC3777658pubmed: 19043408google scholar: lookup
  12. Deeg CA. Immunopathology of recurrent uveitis in spontaneously diseased horses.. Exp Eye Res 2002;75:127–133.
    doi: 10.1006/exer.2002.2011pubmed: 12137758google scholar: lookup
  13. Deeg CA, Reese S, Gerhards H, Wildner G, Kaspers B. The uveitogenic potential of retinal S-antigen in horses.. Invest Ophthalmol Vis Sci 2004;45:2286–2292.
    doi: 10.1167/iovs.03-1226pubmed: 15223807google scholar: lookup
  14. Caspi RR. A look at autoimmunity and inflammation in the eye.. J Clin Invest 2010;120:3073–3083.
    doi: 10.1172/JCI42440pmc: PMC2929721pubmed: 20811163google scholar: lookup
  15. Serrao VH. Promiscuous interactions of human septins: the GTP binding domain of SEPT7 forms filaments within the crystal.. FEBS Lett 2011;585:3868–3873.
    doi: 10.1016/j.febslet.2011.10.043pubmed: 22064074google scholar: lookup
  16. Kim MS, Froese CD, Xie H, Trimble WS. Uncovering principles that control septin-septin interactions.. J Biol Chem 2012;287:30406–30413.
    doi: 10.1074/jbc.M112.387464pmc: PMC3436290pubmed: 22815479google scholar: lookup
  17. Okada S. Daughter cell identity emerges from the interplay of Cdc42, septins, and exocytosis.. Dev Cell 2013;26:148–161.
    doi: 10.1016/j.devcel.2013.06.015pmc: PMC3730058pubmed: 23906065google scholar: lookup
  18. Randall KL. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice.. J Exp Med 2011;208:2305–2320.
    doi: 10.1084/jem.20110345pmc: PMC3201196pubmed: 22006977google scholar: lookup
  19. Zhang Q. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity.. J Exp Med 2014;211:2549–2566.
    doi: 10.1084/jem.20141307pmc: PMC4267229pubmed: 25422492google scholar: lookup
  20. Jabara HH. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.. Nat Immunol 2012;13:612–620.
    doi: 10.1038/ni.2305pmc: PMC3362684pubmed: 22581261google scholar: lookup
  21. Janssen E. A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton.. J Clin Invest 2016;126:3837–3851.
    doi: 10.1172/JCI85774pmc: PMC5096816pubmed: 27599296google scholar: lookup
  22. Pai SY. Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency.. J Allergy Clin Immunol 2014;134:221–223.
    doi: 10.1016/j.jaci.2014.02.023pmc: PMC6317337pubmed: 24698323google scholar: lookup
  23. Hauck SM, Lepper MF, Hertl M, Sekundo W, Deeg CA. Proteome dynamics in biobanked horse peripheral blood derived lymphocytes (PBL) with induced autoimmune uveitis.. Proteomics 2017.
    pubmed: 28846213
  24. Degroote RL. Altered expression of talin 1 in peripheral immune cells points to a significant role of the innate immune system in spontaneous autoimmune uveitis.. J Proteomics 2012;75:4536–4544.
    doi: 10.1016/j.jprot.2012.01.023pubmed: 22306886google scholar: lookup
  25. Liu E. Targeted deletion of integrin-linked kinase reveals a role in T-cell chemotaxis and survival.. Mol Cell Biol 2005;25:11145–11155.
    doi: 10.1128/MCB.25.24.11145-11155.2005pmc: PMC1316981pubmed: 16314534google scholar: lookup
  26. Zhang N. The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.. Oncotarget 2016;7:61587–61600.
    pmc: PMC5308674pubmed: 27557506
  27. Gladfelter AS, Bose I, Zyla TR, Bardes ES, Lew DJ. Septin ring assembly involves cycles of GTP loading and hydrolysis by Cdc42p.. J Cell Biol 2002;156:315–326.
    doi: 10.1083/jcb.200109062pmc: PMC2199227pubmed: 11807094google scholar: lookup
  28. Harada Y. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses.. Blood 2012;119:4451–4461.
    doi: 10.1182/blood-2012-01-407098pmc: PMC3418773pubmed: 22461490google scholar: lookup
  29. Aydin SE. DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients.. J Clin Immunol 2015;35:189–198.
    doi: 10.1007/s10875-014-0126-0pubmed: 25627830google scholar: lookup
  30. Randall KL. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production.. Nat Immunol 2009;10:1283–1291.
    doi: 10.1038/ni.1820pmc: PMC3437189pubmed: 19898472google scholar: lookup
  31. Ham H. Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity.. J Immunol 2013;190:3661–3669.
    doi: 10.4049/jimmunol.1202792pmc: PMC3841075pubmed: 23455509google scholar: lookup
  32. Jing H. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype.. J Allergy Clin Immunol 2014;133:1667–1675.
    doi: 10.1016/j.jaci.2014.03.025pmc: PMC4132167pubmed: 24797421google scholar: lookup
  33. Kearney CJ, Randall KL, Oliaro J. DOCK8 regulates signal transduction events to control immunity.. Cell Mol Immunol 2017;14:406–411.
    doi: 10.1038/cmi.2017.9pmc: PMC5423093pubmed: 28366940google scholar: lookup
  34. Alsum Z. Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients.. J Clin Immunol 2013;33:55–67.
    doi: 10.1007/s10875-012-9769-xpubmed: 22968740google scholar: lookup
  35. Al-Herz W. Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait.. Clin Immunol 2012;143:266–272.
    doi: 10.1016/j.clim.2012.03.002pmc: PMC3893030pubmed: 22534316google scholar: lookup
  36. Janssen E. Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells.. J Allergy Clin Immunol 2014;134:1365–1374.
    doi: 10.1016/j.jaci.2014.07.042pmc: PMC4261031pubmed: 25218284google scholar: lookup
  37. Janssen E. DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs.. JCI Insight 2017.
    pmc: PMC5841868pubmed: 28978806doi: 10.1172/jci.insight.94298google scholar: lookup
  38. Singh AK. DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling.. JCI Insight 2017.
    pmc: PMC5841873pubmed: 28978795doi: 10.1172/jci.insight.94275google scholar: lookup
  39. Rahikainen R. Mechanical stability of talin rod controls cell migration and substrate sensing.. Sci Rep 2017;7:3571.
    doi: 10.1038/s41598-017-03335-2pmc: PMC5472591pubmed: 28620171google scholar: lookup
  40. Degroote RL. Expression changes and novel interaction partners of talin 1 in effector cells of autoimmune uveitis.. J Proteome Res 2013;12:5812–5819.
    doi: 10.1021/pr400837fpubmed: 24144192google scholar: lookup
  41. Ahmed AU, Sarvestani ST, Gantier MP, Williams BR, Hannigan GE. Integrin-linked kinase modulates lipopolysaccharide- and Helicobacter pylori-induced nuclear factor kappaB-activated tumor necrosis factor-alpha production via regulation of p65 serine 536 phosphorylation.. J Biol Chem 2014;289:27776–27793.
    doi: 10.1074/jbc.M114.574541pmc: PMC4183813pubmed: 25100717google scholar: lookup
  42. McDonald PC, Fielding AB, Dedhar S. Integrin-linked kinase–essential roles in physiology and cancer biology.. J Cell Sci 2008;121:3121–3132.
    doi: 10.1242/jcs.017996pubmed: 18799788google scholar: lookup
  43. Nho RS. Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway.. J Biol Chem 2005;280:26630–26639.
    doi: 10.1074/jbc.M411798200pubmed: 15905178google scholar: lookup
  44. Gilger BC, Michau TM. Equine recurrent uveitis: new methods of management.. Vet Clin North Am Equine Pract 2004;20:417–427, vii.
    pubmed: 15271431doi: 10.1016/j.cveq.2004.04.010google scholar: lookup
  45. Hauck SM. Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2.. J Proteomics 2012;75:4545–4554.
    doi: 10.1016/j.jprot.2012.04.052pubmed: 22634081google scholar: lookup
  46. Hauck SM. Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.. Mol Cell Proteomics 2010;9:2292–2305.
    doi: 10.1074/mcp.M110.001073pmc: PMC2953921pubmed: 20601722google scholar: lookup
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.