Cell and Tissue BiologyCell and Tissue BiologyЦитология0041-37713034-6061The Russian Academy of Sciences66956410.31857/S0041377123020116NEQCUAArticlesСтатьиTranscriptional Coactivator BOB1 (OBF1, OCA-B) in Autoimmune DiseasesКоактиватор транскрипции BOB1 (OBF1, OCA-B) в аутоиммунных заболеванияхTomilinA. N.ТомилинА. Н.a.tomilin@incras.ruYeremenkoN. G.ЕременкоН. Г.a.tomilin@incras.ruInstitute of Cytology RASИнститут цитологии РАНUniversity of NantesУниверситет Нанта0103202365211311827022025Copyright ©; 2023, А.Н. Томилин, Н.Г. ЕременкоCopyright ©; 2023, А.Н. Томилин, Н.Г. Еременко2023А.Н. Томилин, Н.Г. ЕременкоА.Н. Томилин, Н.Г. Еременкоhttps://vietnamjournal.ru/0041-3771/article/view/669564

Despite significant efforts in biomedicine for several decades, autoimmune diseases continue to remain largely incurable and, moreover, poorly understood in terms of the molecular mechanisms underlying their onset and progression. It is generally accepted that autoimmune pathologies result from a malfunction of the adaptive immune system in genetically susceptible individuals leading to the appearance of autoreactive B- and T-lymphocytes. However, the exact molecular pathways that drive the activation of autoreactive lymphocytes, leading to the amplification and perpetuation of self-directed immune responses are largely unknown. A number of experimental data accumulated over the past few years indicate a key role of BOB1, namely its imbalanced expression, in the onset of autoreactive lymphocytes. It has been postulated that the coactivator BOB1 affects transcription and local chromatin state indirectly, via selective interaction with DNA-binding POU-domain transcription factors – ubiquitous OCT1 and B-cell-specific OCT2, stabilises the binding of the OCT factors to DNA. The review lists the latest evidences of an important role of BOB1 in pathogenesis of autoimmune diseases and positions this protein as a promising target in the treatment of these diseases.

Аутоиммунные заболевания, несмотря на значительные усилия биомедицины на протяжении уже нескольких десятилетий, продолжают оставаться по большей части неизлечимыми и, более того, плохо понятыми с точки зрения молекулярных механизмов их возникновения и развития. Общепризнано, что в основе этих заболеваний лежит сбой в работе адаптивной иммунной системы, главным атрибутом которого являются аутореактивные B- и Т-лимфоциты. Ряд экспериментальных данных, накопленных за последние несколько лет, свидетельствуют о ключевой роли транскрипционного коактиватора BOB1 в появлении аутореактивных лифоцитов. Постулировано, что BOB1 влияет на транскрипцию и локальный эпигенетический статус хроматина опосредованно, а именно через селективное взаимодействие с ДНК-связывающими POU-доменными транскрипционными факторами – экспрессирующимся во всех клетках OCT1, и специфическим для В-клеток OCT2, стабилизируя связывание этих OCT-факторов с ДНК. В обзоре приведены последние сведения о проаутоиммунной активности BOB1, обозначены перспективы использования этого белка в качестве мишени при разработке фармацевтических препаратов, нацеленных на лечения ряда аутоиммунных заболеваний.

BOB1OCA-BOBF1POU2AF1OCT1OCT2autoimmune diseasesautoreactive T- и B-cellsBOB1OCA-BOBF1Pou2af1OCT1OCT2аутоиммунные заболеванияаутореактивные T- и B-клеткиBetzler A.C., Fiedler K., Hoffmann T.K., Fehling H.J., Wirth T., Brunner C. 2022. BOB.1/OBF.1 is required during B-cell ontogeny for B-cell differentiation and germinal center function. Eur. J Immunol. V. 52. P. 404.Betzler A.C., Fiedler K., Kokai E., Wirth T., Hoffmann T.K., Brunner C. 2021. Impaired Peyer’s patch development in BOB.1/OBF.1-deficient mice. Eur. J. Immunol. V. 51. P. 1860.Brunner C., Sindrilaru A., Girkontaite I., Fischer K.D., Sunderkotter C., Wirth T. 2007. BOB.1/OBF.1 controls the balance of TH1 and TH2 immune responses. EMBO J. V. 26. P. 3191.Brunner C., Wirth T. 2006. Btk expression is controlled by Oct and BOB.1/OBF.1. Nucleic Acids Res. V. 34. P. 1807.Christophersen A., Lund E.G., Snir O., Sola E., Kanduri C., Dahal-Koirala S., Zuhlke S., Molberg O., Utz P.J., Rohani–Pichavant M., Simard J.F., Dekker C.L., Lundin K.E.A., Sollid L.M., Davis M.M. 2019. Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions. Nat. Med. V. 25. P. 734.da Silva F.A.R., Pascoal L.B., Dotti I., Setsuko Ayrizono M.L., Aguilar D., Rodrigues B.L., Arroyes M., Ferrer–Picon E., Milanski M., Velloso L.A., Fagundes J.J., Salas A., Leal R.F. 2020. Whole transcriptional analysis identifies markers of B, T and plasma cell signaling pathways in the mesenteric adipose tissue associated with Crohn’s disease. J. Transl. Med. V. 18. P. 44.Games Collaborative G., Ban M., Booth D., Heard R., Stewart G., Goris A., Vandenbroeck K., Dubois B., Laaksonen M., Ilonen J., Alizadeh M., Edan G., Babron M. C., Brassat D., Clanet M. et al. 2006. Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans. J. Neuroimmunol. V. 179. P. 108.Goris A., Sawcer S., Vandenbroeck K., Carton H., Billiau A., Setakis E., Compston A., Dubois B. 2003. New candidate loci for multiple sclerosis susceptibility revealed by a whole genome association screen in a Belgian population. J. Neuroimmunol. V. 143. P. 65.Hellmuth J.C., Chu C.-S., Singh R., Skrabanek L.A., Doane A., Elemento O., Roeder R.G., Melnick A. 2019. An OCT2/ OCA-B/MEF2B ternary complex controls the activity and architecture of an essential locus control region for normal and malignant germinal center B-cells. Blood. V. 134. Su-ppl. 1. P. 24.Ikegami I., Takaki H., Kamiya S., Kamekura R., Ichimiya S. 2019. Bob1 enhances RORgammat-mediated IL-17A expression in Th17cells through interaction with RORgammat. Biochem. Biophys. Res. Commun. V. 514. P. 1167.Kim H.P., Shakya A., Shen Z., German C., Ibarra A., Jafek J.L., Lin N.-P., Evavold B.D., Chou D.H.-C., Jensen P.E., He X., Tantin D. 2020. Targeting OCA-B/Pou2af1 blocks type-1 diabetes and reduces infiltration of activated, islet-reactive T cells. In bioRxiv.Kim U., Qin X.F., Gong S., Stevens S., Luo Y., Nussenzweig M., Roeder R. G. 1996. The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature. V. 383. P. 542.Levels M.J., Fehres C.M., van Baarsen L.G.M., van Uden N.O.P., Germar K., O’Toole T.G., Blijdorp I.C.J., Semmelink J.F., Doorenspleet M.E., Bakker A.Q., Krasavin M., Tomilin A., Brouard S., Spits H., Baeten D.L.P., Yeremenko N.G. 2019. BOB.1 controls memory B-cell fate in the germinal center reaction. J. Autoimmun. V. 101. P. 131.Levels M.J., Van Tok M.N., Cantaert T., Canete J.D., Kroese F.G., Germar K., Spits H., Baeten D.L., Yeremenko N.G. 2017. The transcriptional coactivator Bob1 is associated with pathologic B cell responses in autoimmune tissue inflammation. Arthritis Rheumatol. V. 69. P. 750.Lombard-Vadnais F., Lacombe J., Chabot-Roy G., Ferron M., Lesage S. 2022. OCA-B does not act as a transcriptional coactivator in T cells. Immunol. Cell Biol. V. 100. P. 338.McDonough J.E., Ahangari F., Li Q., Jain S., Verleden S.E., Herazo-Maya J., Vukmirovic M., DeIuliis G., Tzouvelekis A., Tanabe N., Chu F., Yan X., Verschakelen J., Homer R. J., Manatakis D.V., et al. 2019. Transcriptional regulatory model of fibrosis progression in the human lung. JCI Insight. V. 4. e131597.Moriuchi M., Moriuchi H. 2001. Octamer transcription factors up-regulate the expression of CCR5, a coreceptor for HIV-1 entry. J. Biol. Chem. V. 276. P. 8639.Nakamura M., Nishida N., Kawashima M., Aiba Y., Tanaka A., Yasunami M., Nakamura H., Komori A., Nakamuta M., Zeniya M., Hashimoto E., Ohira H., Yamamoto K., Onji M., Kaneko S. et al. 2012. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am. J. Hum. Genet. V. 91. P. 721.Nielsen P.J., Georgiev O., Lorenz B., Schaffner W. 1996. B lymphocytes are impaired in mice lacking the transcriptional co-activator Bob1/OCA-B/OBF1. Eur. J. Immunol. V. 26. P. 3214.Rao D.A., Gurish M.F., Marshall J.L., Slowikowski K., Fonseka C.Y., Liu Y., Donlin L.T., Henderson L.A., Wei K., Mizoguchi F., Teslovich N.C., Weinblatt M.E., Massarotti E.M., Coblyn J.S., Helfgott S.M. et al. 2017. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. V. 542. P. 110.Sauter P., Matthias P. 1997. The B cell-specific coactivator OBF-1 (OCA-B, Bob-1) is inducible in T cells and its expression is dispensable for IL-2 gene induction. Immunobiology. V. 198. P. 207.Schubart D.B., Rolink A., Kosco–Vilbois M.H., Botteri F., Matthias P. 1996. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature. V. 383. P. 538.Shakya A., Goren A., Shalek A., German C. N., Snook J., Kuchroo V.K., Yosef N., Chan R.C., Regev A., Williams M.A., Tantin D. 2015. Oct1 and OCA-B are selectively required for CD4 memory T cell function. J. Exp. Med. V. 212. P. 2115.Shirai Y., Nakanishi Y., Suzuki A., Konaka H., Nishikawa R., Sonehara K., Namba S., Tanaka H., Masuda T., Yaga M., Satoh S., Izumi M., Mizuno Y., Jo T., Maeda Y. et al. 2022. Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component. Ann. Rheum. Dis. V. 81. P. 1301.Song S., Cao C., Choukrallah M.A., Tang F., Christofori G., Kohler H., Wu F., Fodor B.D., Frederiksen M., Willis S.N., Jackson J.T., Nutt S.L., Dirnhofer S., Stadler M.B., Matthias P. 2021. OBF1 and Oct factors control the germinal center transcriptional program. Blood. V. 137. P. 2920.Sun W., Kim H., Perovanovic J., Hughes E., Du J., Ibarra A., Scott J.H., Williams M.A., Tantin D. 2022. Transcription coactivator OCA-B/Pou2af1 is necessary and sufficient to promote T cell-intrinsic CD4 memory. BioRxiv. https:// www.biorxiv.org/content/10.1101/2022.09.21.508912v1.Sun J., Matthias G., Mihatsch M.J., Georgopoulos K., Matthias P. 2003. Lack of the transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. J. Immunol. V. 170. P. 1699.Teitell M.A. 2003. OCA-B regulation of B-cell development and function. Trends Immunol. V. 24. P. 546.Trynka G., Hunt K.A., Bockett N.A., Romanos J., Mistry V., Szperl A., Bakker S.F., Bardella M.T., Bhaw-Rosun L., Castillejo G., de la Concha E.G., de Almeida R.C., Dias K.R., van Diemen C.C., Dubois P.C. et al. 2011. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. V. 43. P. 1193.Yamashita K., Kawata K., Matsumiya H., Kamekura R., Jitsukawa S., Nagaya T., Ogasawara N., Takano K., Kubo T., Kimura S., Shigehara K., Himi T., Ichimiya S. 2016. Bob1 limits cellular frequency of T-follicular helper cells. Eur. J. Immunol. V. 46. P. 1361.Yeremenko N., Danger R., Baeten D., Tomilin A., Brouard S. 2021. Transcriptional regulator BOB.1: Molecular mechanisms and emerging role in chronic inflammation and autoimmunity. Autoimmun. Rev. V. 20. P. 102833.Zuo J., Ge H., Zhu G., Matthias P., Sun J. 2007. OBF-1 is essential for the generation of antibody-secreting cells and the development of autoimmunity in MRL-lpr mice. J. Autoimmun. V. 29. P. 87.Zwilling S., Dieckmann A., Pfisterer P., Angel P., Wirth T. 1997. Inducible expression and phosphorylation of coactivator BOB.1/OBF.1 in T cells. Science. V. 277. P. 221.