Cell and Tissue BiologyCell and Tissue BiologyЦитология0041-37713034-6061The Russian Academy of Sciences66964410.31857/S0041377123030069VDORORArticlesСтатьиUbiquitin–Proteasome System in Cell Pluripotency and DifferentiationУбиквитин-протеасомная система в регуляции клеточной плюрипотентности и дифференцировкиPodenkovaU. I.ПоденковаУ. И.atsimokha@incras.ruZubarevI. V.ЗубаревИ. В.atsimokha@incras.ruTomilinA. N.ТомилинА. Н.atsimokha@incras.ruTsimokhaA. S.ЦимохаА. С.atsimokha@incras.ruInstitute of Cytology, Russian Academy of SciencesИнститут цитологии РАН0105202365323224527022025Copyright ©; 2023, У.И. Поденкова, И.В. Зубарев, А.Н. Томилин, А.С. ЦимохаCopyright ©; 2023, У.И. Поденкова, И.В. Зубарев, А.Н. Томилин, А.С. Цимоха2023У.И. Поденкова, И.В. Зубарев, А.Н. Томилин, А.С. ЦимохаУ.И. Поденкова, И.В. Зубарев, А.Н. Томилин, А.С. Цимохаhttps://vietnamjournal.ru/0041-3771/article/view/669644

Pluripotent stem cells (PSCs), represented primarily by embryonic stem cells and induced pluripotent stem cells (iPSCs), have a unique ability to self-renew and differentiate into all types of somatic cells. Dissecting molecular mechanisms controlling these properties is important for an efficient and safe introduction of PSCs into clinics. Growing evidence indicates that the proteostasis plays a central role in PSCs fate decisions. This review focuses on the role of the ubiquitin-proteasome system, a key member of the proteostasis network, in the regulation of pluripotency and differentiation of PSCs.

Эмбриональные стволовые клетки (ЭСК) и индуцированные плюрипотентные стволовые клетки (иПСК) демонстрируют уникальную способность к непрерывному самообновлению и дифференцировке во все типы соматических клеток. Понимание механизмов, контролирующих эти свойства, приблизит к эффективному и безопасному использованию ЭСК и иПСК в клеточной терапии. Недавние совокупные данные подчеркнули важность протеостаза в поддержании функции ЭСК. Настоящий обзор посвящен роли убиквитин-протеасомной системы (УПС) – ключевого участника сети протеостаза – в регуляции плюрипотентности и дифференцировки ЭСК и иПСК.

deubiquitinasesdifferentiationembryonic stem cellspluripotencyproteasomeubiquitin ligasesubiquitin–proteasome systemдеубиквитиназыдифференцировкаплюрипотентностьпротеасомаубиквитин-лигазыубиквитин-протеасомная системаэмбриональные стволовые клеткиГордеев М.Н., Бахмет Е.И., Томилин А.Н. 2021. Динамика плюрипотентности в эмбриогенезе и в культуре. Онтогенез. Т. 52. № 6. С. 429. (Gordeev M., Bakhmet E., Tomilin A. 2021. Pluripotency dynamics during embryogenesis and in cell culture. Russ. J. Dev. Biol. V. 52. № 6. P. 379.)https://doi.org/10.1134/S1062360421060059Селенина А.В., Цимоха А.С., Томилин А.Н. 2017. Протеасомы в регуляции белкового гомеостаза плюрипотентных стволовых клеток. Acta Naturae. Т. 9. № 3. С. 42. (Selenina A.V., Tsimokha A.S., Tomilin A.N. 2017. Proteasomes in protein homeostasis of pluripotent stem cells. Acta Naturae. V. 9. № 3. P. 42.)Abu-Dawud R., Graffmann N., Ferber S., Wruck W., Adjaye J. 2018. Pluripotent stem cells: induction and self-renewal. Philos. Trans. R. Soc. Lond. B Biol. Sci. V. 373. P. 20170213. https://doi.org/10.1098/rstb.2017.0213Al Mamun M.M., Khan M.R., Zhu Y., Zhang Y., Zhou S., Xu R., Bukhari I., Thorne R.F., Li J., Zhang X.D. 2022. Stub1 maintains proteostasis of master transcription factors in embryonic stem cells. Cell Rep. V. 39. P. 110919. https://doi.org/10.1016/j.celrep.2022.110919Alekseenko Z., Dias J.M., Adler A.F., Kozhevnikova M., van Lunteren J.A., Nolbrant S., Jeggari A., Vasylovska S., Yoshitake T., Kehr J. 2022. Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery. Nature Commun. V.13. P. 1. https://doi.org/10.1038/s41467-022-30777-8Babaie Y., Herwig R., Greber B., Brink T.C., Wruck W., Groth D., Lehrach H., Burdon T., Adjaye J. 2007. Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells. Stem Cells. V. 25. P. 500. https://doi.org/10.1634/stemcells.2006-0426Baharvand H., Hajheidari M., Ashtiani S.K., Salekdeh G.H. 2006. Proteomic signature of human embryonic stem cells. Proteomics. V. 6. P. 3544. https://doi.org/10.1002/pmic.200500844Bai M., Zhao X., Sahara K., Ohte Y., Hirano Y., Kaneko T., Yashiroda H., Murata S. 2014. Assembly mechanisms of specialized core particles of the proteasome. Biomolecules. V. 4. P. 662. https://doi.org/10.3390/biom4030662Beckwith R., Estrin E., Worden E.J., Martin A. 2013. Reconstitution of the 26S proteasome reveals functional asymmetries in its AAA+ unfoldase. Nat. Struct. Mol. Biol. V. 20. P. 1164. https://doi.org/10.1038/nsmb.2659Behbahan I.S., Duan Y., Lam A., Khoobyari S., Ma X., Ahuja T.P., Zern M.A. 2011. New approaches in the differentiation of human embryonic stem cells and induced pluripotent stem cells toward hepatocytes. Stem Cell Rev. Rep. V. 7. P. 748. https://doi.org/10.1007/s12015-010-9216-4Bernstein B.E., Mikkelsen T.S., Xie X., Kamal M., Huebert D.J., Cuff J., Fry B., Meissner A., Wernig M., Plath K. 2006. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. V. 125. P. 315. https://doi.org/10.1016/j.cell.2006.02.041Biancotti J.C., Narwani K., Buehler N., Mandefro B., Golan-Lev T., Yanuka O., Clark A., Hill D., Benvenisty N., Lavon N. 2010. Human embryonic stem cells as models for aneuploid chromosomal syndromes. Stem Cells. V. 28. P. 1530. https://doi.org/10.1002/stem.483Blondelle J., Shapiro P., Domenighetti A.A., Lange S. 2017. Cullin E3 ligase activity is required for myoblast differentiation. J. Mol. Biol. V. 429. P. 1045. https://doi.org/10.1016/j.jmb.2017.02.012Buckley S.M., Aranda-Orgilles B., Strikoudis A., Apostolou E., Loizou E., Moran-Crusio K., Farnsworth C.L., Koller A.A., Dasgupta R., Silva J.C., Stadtfeld M., Hochedlinger K., Chen E.I., Aifantis I. 2012. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell. V. 11. P. 783. https://doi.org/10.1016/j.stem.2012.09.011Budenholzer L., Cheng C.L., Li Y., Hochstrasser M. 2017. Proteasome Structure and Assembly. J. Mol. Biol. V. 429. P. 3500. https://doi.org/10.1016/j.jmb.2017.05.027Bustos F., Segarra-Fas A., Chaugule V.K., Brandenburg L., Branigan E., Toth R., Macartney T., Knebel A., Hay R.T., Walden H. 2018. RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. Cell Rep. V. 23. P. 1599. https://doi.org/10.1016/j.celrep.2018.04.022Cao F., Lin S., Xie X., Ray P., Patel M., Zhang X., Drukker M., Dylla S.J., Connolly A.J., Chen X. 2006. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation. V. 113. P. 1005. https://doi.org/10.1161/CIRCULATIONAHA.105.588954Cascio P., Hilton C., Kisselev A.F., Rock K.L., Goldberg A.L. 2001. 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J. V. 20. P. 2357. https://doi.org/10.1093/emboj/20.10.2357Choi J., Baek K.H. 2018. Cellular functions of stem cell factors mediated by the ubiquitin-proteasome system. Cell. Mol. Life Sci. V. 75. P. 1947. https://doi.org/10.1007/s00018-018-2770-7Ciechanover A., Kwon Y.T. 2015. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp. Mol. Med. V. 47. P. e147. https://doi.org/10.1038/emm.2014.117Cui Z., Hwang S.M., Gomes A.V. 2014. Identification of the immunoproteasome as a novel regulator of skeletal muscle differentiation. Mol. Cell. Biol. V. 34. P. 96. https://doi.org/10.1128/MCB.00622-13Dahlmann B. 2005. Proteasomes. Essays Biochem. V. 41. P. 31. https://doi.org/10.1042/EB0410031de Napoles M., Mermoud J.E., Wakao R., Tang Y.A., Endoh M., Appanah R., Nesterova T.B., Silva J., Otte A.P., Vidal M. 2004. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell. V. 7. P. 663. https://doi.org/10.1016/j.devcel.2004.10.005Diefenbacher M.E., Chakraborty A., Blake S.M., Mitter R., Popov N., Eilers M., Behrens A. 2015. Usp28 counteracts Fbw7 in intestinal homeostasis and cancer. Cancer Res. V. 75. P. 1181. https://doi.org/10.1158/0008-5472.CAN-14-1726Dieudonne F.-X., Sévère N., Biosse-Duplan M., Weng J.-J., Su Y., Marie P.J. 2013. Promotion of osteoblast differentiation in mesenchymal cells through Cbl-mediated control of STAT5 activity. Stem Cells. V. 31. P. 1340. https://doi.org/10.1002/stem.1380Drews O., Taegtmeyer H. 2014. Targeting the ubiquitin-proteasome system in heart disease: the basis for new therapeutic strategies. Antioxid. Redox. Signal. V. 21. P. 2322. https://doi.org/10.1089/ars.2013.5823Du Z., He F., Yu Z., Bowerman B., Bao Z. 2015. E3 ubiquitin ligases promote progression of differentiation during C. elegans embryogenesis. Dev. Biol. V. 398. P. 267. https://doi.org/10.1016/j.ydbio.2014.12.009Dutta D., Sharma V., Mutsuddi M., Mukherjee A. 2021. Regulation of Notch signaling by E3 ubiquitin ligases. FEBS J. V. 289. P. 937. https://doi.org/10.1111/febs.15792Endoh M., Endo T.A., Endoh T., Fujimura Y.-I., Ohara O., Toyoda T., Otte A.P., Okano M., Brockdorff N., Vidal M. 2008. Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development. V. 135. P. 1513. https://doi.org/10.1242/dev.014340Fabre B., Lambour T., Garrigues L., Amalric F., Vigneron N., Menneteau T., Stella A., Monsarrat B., Van den Eynde B., Burlet-Schiltz O. 2015. Deciphering preferential interactions within supramolecular protein complexes: the proteasome case. Mol. Syst. Biol. V. 11. P. 771. https://doi.org/10.15252/msb.20145497Fang L., Zhang L., Wei W., Jin X., Wang P., Tong Y., Li J., Du J.X., Wong J. 2014. A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation. Mol. Cell. V. 55. P. 537. https://doi.org/10.1016/j.molcel.2014.06.018Finley D., Tanaka K., Mann C., Feldmann H., Hochstrasser M., Vierstra R., Johnston S., Hampton R., Haber J., McCusker J., Silver P., Frontali L., Thorsness P., Varshavsky A., Byers B. et al. 1998. Unified nomenclature for subunits of the Saccharomyces cerevisiae proteasome regulatory particle. Trends Biochem. Sci. V. 23. P. 244. https://doi.org/10.1016/s0968-0004(98)01222-5Fort P., Kajava A.V., Delsuc F., Coux O. 2015. Evolution of proteasome regulators in eukaryotes. Genome Biol. Evol. V. 7. P. 1363. https://doi.org/10.1093/gbe/evv068Fu X. 2014. The immunogenicity of cells derived from induced pluripotent stem cells. Cell. Mol. Immunol. V. 11. P. 14. https://doi.org/10.1038/cmi.2013.60Fuchs G., Shema E., Vesterman R., Kotler E., Wolchinsky Z., Wilder S., Golomb L., Pribluda A., Zhang F., Haj-Yahya M., Feldmesser E., Brik A., Yu X., Hanna J., Aberdam D., Domany E., Oren M. 2012. RNF20 and USP44 regulate stem cell differentiation by modulating H2B monoubiquitylation. Mol. Cell. V. 46. P. 662. https://doi.org/10.1016/j.molcel.2012.05.023Fujikawa T., Oh S.-H., Pi L., Hatch H.M., Shupe T., Petersen B.E. 2005. Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. Am. J. Pathol. V. 166. P. 1781. https://doi.org/10.1016/S0002-9440(10)62488-1Gao C., Xiao G., Hu J. 2014. Regulation of Wnt/β-catenin signaling by posttranslational modifications. Cell Biosci. V. 4. P. 13. https://doi.org/10.1186/2045-3701-4-13Gao J., Buckley S.M., Cimmino L., Guillamot M., Strikoudis A., Cang Y., Goff S.P., Aifantis I. 2015. The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. Elife. V. 4. P. e07539. https://doi.org/10.7554/eLife.07539Glickman M.H., Rubin D.M., Coux O., Wefes I., Pfeifer G., Cjeka Z., Baumeister W., Fried V. A., Finley D. 1998. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell. V. 94. P. 615. https://doi.org/10.1016/s0092-8674(00)81603-7Groll M., Bajorek M., Kohler A., Moroder L., Rubin D.M., Huber R., Glickman M.H., Finley D. 2000. A gated channel into the proteasome core particle. Nat. Struct. Biol. V. 7. P. 1062. https://doi.org/10.1038/80992Groll M., Bochtler M., Brandstetter H., Clausen T., Huber R. 2005. Molecular machines for protein degradation. Chembiochem. V. 6. P. 222. https://doi.org/10.1002/cbic.200400313Groll M., Ditzel L., Lowe J., Stock D., Bochtler M., Bartunik H.D., Huber R. 1997. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. V. 386. P. 463. https://doi.org/10.1038/386463a0Hatakeyama S. 2012. Ubiquitin-mediated regulation of JAK-STAT signaling in embryonic stem cells. JAKSTAT. V. 1. P. 168. https://doi.org/10.4161/jkst.21560Hayashi K., de Sousa Lopes S.M.C., Tang F., Surani M.A. 2008. Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell. V. 3. P. 391. https://doi.org/10.1016/j.stem.2008.07.027He M., Zhou Z., Shah A.A., Zou H., Tao J., Chen Q., Wan Y. 2016. The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics. Cell Biosci. V. 6. P. 62. https://doi.org/10.1186/s13578-016-0127-1Hernebring M., Brolen G., Aguilaniu H., Semb H., Nystrom T. 2006. Elimination of damaged proteins during differentiation of embryonic stem cells. Proc. Natl. Acad. Sci. USA. V. 103. P. 7700. https://doi.org/10.1073/pnas.0510944103Hernebring M., Fredriksson A., Liljevald M., Cvijovic M., Norrman K., Wiseman J., Semb H., Nystrom T. 2013. Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28. Sci. Rep. V. 3. P. 1381. https://doi.org/10.1038/srep01381Hershko A., Ciechanover A. 1992. The ubiquitin system for protein degradation. Annu. Rev. Biochem. V. 61. P. 761. https://doi.org/10.1146/annurev.bi.61.070192.003553Hershko A., Ciechanover A. 1998. The ubiquitin system. Annu. Rev. Biochem. V. 67. P. 425. https://doi.org/10.1146/annurev.biochem.67.1.425Inoue D., Aihara H., Sato T., Mizusaki H., Doiguchi M., Higashi M., Imamura Y., Yoneda M., Miyanishi T., Fujii S. 2015. Dzip3 regulates developmental genes in mouse embryonic stem cells by reorganizing 3D chromatin conformation. Sci. Rep. V. 5. P. 16567. https://doi.org/10.1038/srep16567Jiang T.X., Zhao M., Qiu X.B. 2018. Substrate receptors of proteasomes. Biol. Rev. Camb. Philos. Soc. V. 93. P. 1765. https://doi.org/10.1111/brv.12419Jing X., Infante J., Nachtman R.G., Jurecic R. 2008. E3 ligase FLRF (Rnf41) regulates differentiation of hematopoietic progenitors by governing steady-state levels of cytokine and retinoic acid receptors. Exp. Hematol. V. 36. P. 1110. https://doi.org/10.1016/j.exphem.2008.04.001Kammerl I.E., Dann A., Mossina A., Brech D., Lukas C., Vosyka O., Nathan P., Conlon T.M., Wagner D.E., Overkleeft H.S. 2016. Impairment of immunoproteasome function by cigarette smoke and in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. V. 193. P. 1230. https://doi.org/10.1164/rccm.201506-1122OCKim S.-H., Kim M.O., Cho Y.-Y., Yao K., Kim D.J., Jeong C.-H., Yu D.H., Bae K.B., Cho E.J., Jung S.K. 2014. ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal. Stem Cell Res. V. 13. P. 1. https://doi.org/10.1016/j.scr.2014.04.001Konstantinova I.M., Tsimokha A.S., Mittenberg A.G. 2008. Role of proteasomes in cellular regulation. Int. Rev. Cell. Mol. Biol. V. 267. P. 59. https://doi.org/10.1016/S1937-6448(08)00602-3Li S., Xiao F., Zhang J., Sun X., Wang H., Zeng Y., Hu J., Tang F., Gu J., Zhao Y., Jin Y., Liao B. 2018. Disruption of OCT4 ubiquitination increases OCT4 protein stability and ASH2L-B-mediated H3K4 methylation promoting pluripotency acquisition. Stem Cell Reports. V. 11. P. 973. https://doi.org/10.1016/j.stemcr.2018.09.001Liao B., Zhong X., Xu H., Xiao F., Fang Z., Gu J., Chen Y., Zhao Y., Jin Y. 2013. Itch, an E3 ligase of Oct4, is required for embryonic stem cell self-renewal and pluripotency induction. J. Cell. Physiol. V. 228. P. 1443. https://doi.org/10.1002/jcp.24297Liu X., Yao Y., Ding H., Han C., Chen Y., Zhang Y., Wang C., Zhang X., Zhang Y., Zhai Y. 2016. USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency. Signal Transduct. Target. Ther. V. 1. P. 16024. https://doi.org/10.1038/sigtrans.2016.24Liu Y.-J., Nakamura T., Nakano T. 2012. Essential role of DPPA3 for chromatin condensation in mouse oocytogenesis. Biol. Reprod. V. 86. P. 40. https://doi.org/10.1095/biolreprod.111.095018Liu Y., Xu H.W., Wang L., Li S.Y., Zhao C.J., Hao J., Li Q.Y., Zhao T.T., Wu W., Wang Y. 2018. Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular degeneration. Cell Discov. V. 4. P. 50. https://doi.org/10.1038/s41421-018-0053-yMattout A., Meshorer E. 2010. Chromatin plasticity and genome organization in pluripotent embryonic stem cells. Curr. Opin. Cell Biol. V. 22. P. 334. https://doi.org/10.1016/j.ceb.2010.02.001Meiners S., Keller I.E., Semren N., Caniard A. 2014. Regulation of the proteasome: evaluating the lung proteasome as a new therapeutic target. Antioxid. Redox. Signal. V. 21. P. 2364. https://doi.org/10.1089/ars.2013.5798Meiners S., Ludwig A., Stangl V., Stangl K. 2008. Proteasome inhibitors: poisons and remedies. Med. Res. Rev. V. 28. P. 309. https://doi.org/10.1002/med.20111Meshorer E., Misteli T. 2006. Chromatin in pluripotent embryonic stem cells and differentiation. Nat. Rev. Mol. Cell Biol. V. 7. P. 540. https://doi.org/10.1038/nrm1938Miyazono K. 2000. TGF-β signaling by Smad proteins. Cytokine Growth Factor Rev. V. 11. P. 15. https://doi.org/10.1016/s1359-6101(99)00025-8Morozov A.V., Karpov V.L. 2018. Biological consequences of structural and functional proteasome diversity. Heliyon. V. 4. P. e00894. https://doi.org/10.1016/j.heliyon.2018.e00894Murata S., Takahama Y., Tanaka K. 2008. Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. V. 20. P. 192. https://doi.org/10.1016/j.coi.2008.03.002Nakagawa T., Kajitani T., Togo S., Masuko N., Ohdan H., Hishikawa Y., Koji T., Matsuyama T., Ikura T., Muramatsu M. 2008. Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di-and trimethylation. Genes Dev. V. 22. P. 37. https://doi.org/10.1101/gad.1609708Nakamura T., Arai Y., Umehara H., Masuhara M., Kimura T., Taniguchi H., Sekimoto T., Ikawa M., Yoneda Y., Okabe M. 2007. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat. Cell Biol. V. 9. P. 64. https://doi.org/10.1038/ncb1519Nakamura T., Liu Y.-J., Nakashima H., Umehara H., Inoue K., Matoba S., Tachibana M., Ogura A., Shinkai Y., Nakano T. 2012. PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. V. 486. P. 415. https://doi.org/10.1038/nature11093Nandi D., Tahiliani P., Kumar A., Chandu D. 2006. The ubiquitin-proteasome system. J. Biosci. V. 31. P. 137. https://doi.org/10.1007/BF02705243Ng H.-H., Surani M.A. 2011. The transcriptional and signalling networks of pluripotency. Nat. Cell Biol. V. 13. P. 490. https://doi.org/10.1038/ncb0511-490Nguyen D.T.T., Richter D., Michel G., Mitschka S., Kolanus W., Cuevas E., Wulczyn F.G. 2017. The ubiquitin ligase LIN41/TRIM71 targets p53 to antagonize cell death and differentiation pathways during stem cell differentiation. Cell Death Differ. V. 24. P. 1063. https://doi.org/10.1038/cdd.2017.54Noormohammadi A., Calculli G., Gutierrez-Garcia R., Khodakarami A., Koyuncu S., Vilchez D. 2018. Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cell. Mol. Life Sci. V. 75. P. 275. https://doi.org/10.1007/s00018-017-2602-1Okita Y., Matsumoto A., Yumimoto K., Isoshita R., Nakayama K.I. 2012. Increased efficiency in the generation of induced pluripotent stem cells by F bxw7 ablation. Genes Cells. V. 17. P. 768. https://doi.org/10.1111/j.1365-2443.2012.01626.xOkita Y., Nakayama K.I. 2012. UPS delivers pluripotency. Cell Stem Cell. V. 11. P. 728. https://doi.org/10.1016/j.stem.2012.11.009Okumura F., Matsunaga Y., Katayama Y., Nakayama K.I., Hatakeyama S. 2010. TRIM8 modulates STAT3 activity through negative regulation of PIAS3. J. Cell Sci. V. 123. P. 2238. https://doi.org/10.1242/jcs.068981Osmulski P.A., Hochstrasser M., Gaczynska M. 2009. A tetrahedral transition state at the active sites of the 20S proteasome is coupled to opening of the alpha-ring channel. Structure. V. 17. P. 1137. https://doi.org/10.1016/j.str.2009.06.011Pak C., Danko T., Zhang Y., Aoto J., Anderson G., Maxeiner S., Yi F., Wernig M., Südhof T.C. 2015. Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. Cell Stem Cell. V. 17. P. 316. https://doi.org/10.1016/j.stem.2015.07.017Pan J., Deng Q., Jiang C., Wang X., Niu T., Li H., Chen T., Jin J., Pan W., Cai X., Yang X., Lu M., Xiao J., Wang P. 2015. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene. V. 34. P. 3957. https://doi.org/10.1038/onc.2014.327Pickering A.M., Davies K.J. 2012. Degradation of damaged proteins: the main function of the 20S proteasome. Prog. Mol. Biol. Transl. Sci. V. 109. P. 227. https://doi.org/10.1016/B978-0-12-397863-9.00006-7Qian M.X., Pang Y., Liu C.H., Haratake K., Du B.Y., Ji D.Y., Wang G.F., Zhu Q.Q., Song W., Yu Y., Zhang X.X., Huang H.T., Miao S., Chen L.B., Zhang Z.H., Liang Y.N. et al. 2013. Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell. V. 153. P. 1012. https://doi.org/10.1016/j.cell.2013.04.032Rezania A., Bruin J.E., Arora P., Rubin A., Batushansky I., Asadi A., O’dwyer S., Quiskamp N., Mojibian M., Albrecht T. 2014. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. V. 32. P. 1121. https://doi.org/10.1038/nbt.3033Sang H., Wang D., Zhao S., Zhang J., Zhang Y., Xu J., Chen X., Nie Y., Zhang K., Zhang S. 2019. Dppa3 is critical for Lin28a-regulated ES cells naïve–primed state conversion. J. Mol. Cell Biol. V. 11. P. 474. https://doi.org/10.1093/jmcb/mjy069Saretzki G., Armstrong L., Leake A., Lako M., von Zglinicki T. 2004. Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells. V. 22. P. 962. https://doi.org/10.1634/stemcells.22-6-962Saric T., Chang S.-C., Hattori A., York I.A., Markant S., Rock K.L., Tsujimoto M., Goldberg A.L. 2002. An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides. Nat. Immunol. V. 3. P. 1169. https://doi.org/10.1038/ni859Sato N., Sanjuan I.M., Heke M., Uchida M., Naef F., Brivanlou A.H. 2003. Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev. Biol. V. 260. P. 404. https://doi.org/10.1016/s0012-1606(03)00256-2Schuldiner M., Eiges R., Eden A., Yanuka O., Itskovitz-Eldor J., Goldstein R.S., Benvenisty N. 2001. Induced neuronal differentiation of human embryonic stem cells. Brain Res. V. 913. P. 201. https://doi.org/10.1016/s0006-8993(01)02776-7Schwartz S.D., Regillo C.D., Lam B.L., Eliott D., Rosenfeld P.J., Gregori N.Z., Hubschman J.-P., Davis J.L., Heilwell G., Spirn M. 2015. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. V. 385. P. 509. https://doi.org/10.1016/S0140-6736(14)61376-3Seemuller E., Lupas A., Stock D., Lowe J., Huber R., Baumeister W. 1995. Proteasome from Thermoplasma acidophilum: a threonine protease. Science. V. 268. P. 579. https://doi.org/10.1126/science.7725107Sinenko S.A., Starkova T.Y., Kuzmin A.A., Tomilin A.N. 2021. Physiological signaling functions of reactive oxygen species in stem cells: From flies to man. Front. Cell Dev. Biol. V. 9. P. 714370. https://doi.org/10.3389/fcell.2021.714370Smalle J., Vierstra R.D. 2004. The ubiquitin 26S proteasome proteolytic pathway. Annu. Rev. Plant Biol. V. 55. P. 555. https://doi.org/10.1146/annurev.arplant.55.031903.141801Stadtmueller B.M., Hill C.P. 2011. Proteasome activators. Mol. Cell. V. 41. P. 8. https://doi.org/10.1016/j.molcel.2010.12.020Sun X.X., He X., Yin L., Komada M., Sears R.C., Dai M.S. 2015. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc. Natl. Acad. Sci. USA. V. 112. P. 3734. https://doi.org/10.1073/pnas.1411713112Suresh B., Lee J., Kim K.S., Ramakrishna S. 2016. The importance of ubiquitination and deubiquitination in cellular reprogramming. Stem Cells Int. V. 2016. P. 6705927. https://doi.org/10.1155/2016/6705927Takahashi K., Yamanaka S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. V. 126. P. 663. https://doi.org/10.1016/j.cell.2006.07.024Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. 1998. Embryonic stem cell lines derived from human blastocysts. Science. V. 282. P. 1145. https://doi.org/10.1126/science.282.5391.1145Uechi H., Hamazaki J., Murata S. 2014. Characterization of the testis-specific proteasome subunit alpha4s in mammals. J. Biol. Chem. V. 289. P. 12365. https://doi.org/10.1074/jbc.M114.558866Urbach A., Benvenisty N. 2009. Studying early lethality of 45, XO (Turner’s syndrome) embryos using human embryonic stem cells. PLoS One. V. 4. P. e4175. https://doi.org/10.1371/journal.pone.0004175Uyama M., Sato M.M., Kawanami M., Tamura M. 2012. Regulation of osteoblastic differentiation by the proteasome inhibitor bortezomib. Genes Cells. V. 17. P. 548. https://doi.org/10.1111/j.1365-2443.2012.01611.xvan der Stoop P., Boutsma E.A., Hulsman D., Noback S., Heimerikx M., Kerkhoven R.M., Voncken J.W., Wessels L.F., van Lohuizen M. 2008. Ubiquitin E3 ligase Ring1b/Rnf2 of polycomb repressive complex 1 contributes to stable maintenance of mouse embryonic stem cells. PLoS One. V. 3. P. e2235. https://doi.org/10.1371/journal.pone.0002235Verma R., Aravind L., Oania R., McDonald W.H., Yates J.R., 3rd, Koonin E.V., Deshaies R.J. 2002. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science. V. 298. P. 611. https://doi.org/10.1126/science.1075898Vilchez D., Boyer L., Lutz M., Merkwirth C., Morantte I., Tse C., Spencer B., Page L., Masliah E., Berggren W.T., Gage F.H., Dillin A. 2013. FOXO4 is necessary for neural differentiation of human embryonic stem cells. Aging Cell. V. 12. P. 518. https://doi.org/10.1111/acel.12067Vilchez D., Boyer L., Morantte I., Lutz M., Merkwirth C., Joyce D., Spencer B., Page L., Masliah E., Berggren W.T., Gage F.H., Dillin A. 2012a. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature. V. 489. P. 304. https://doi.org/10.1038/nature11468Vilchez D., Morantte I., Liu Z., Douglas P.M., Merkwirth C., Rodrigues A.P., Manning G., Dillin A. 2012b. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature. V. 489. P. 263. https://doi.org/10.1038/nature11315Voutsadakis I.A. 2012. The ubiquitin–proteasome system and signal transduction pathways regulating epithelial mesenchymal transition of cancer. J. Biomed. Sci. V. 19. P. 67. https://doi.org/10.1186/1423-0127-19-67Wang D., Bu F., Zhang W. 2019. The role of ubiquitination in regulating embryonic stem cell maintenance and cancer development. Int. J. Mol. Sci. V. 20. P. 2667. https://doi.org/10.3390/ijms20112667Wang X., Meul T., Meiners S. 2020. Exploring the proteasome system: a novel concept of proteasome inhibition and regulation. Pharmacol. Ther. V. 211. P. 107526. https://doi.org/10.1016/j.pharmthera.2020.107526Watanabe M., Takahashi H., Saeki Y., Ozaki T., Itoh S., Suzuki M., Mizushima W., Tanaka K., Hatakeyama S. 2015. The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARγ. Elife. V. 4. P. e05615. https://doi.org/10.7554/eLife.05615Weitzman M.D., Lilley C.E., Chaurushiya M.S. 2010. Genomes in conflict: maintaining genome integrity during virus infection. Annu. Rev. Microbiol. V. 64. P. 61. https://doi.org/10.1146/annurev.micro.112408.134016Werner A., Manford A.G., Rape M. 2017. Ubiquitin-dependent regulation of stem cell biology. Trends Cell Biol. V. 27. P. 568. https://doi.org/10.1016/j.tcb.2017.04.002Xiao N., Eto D., Elly C., Peng G., Crotty S., Liu Y.-C. 2014. The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat. Immunol. V. 15. P. 657. https://doi.org/10.1038/ni.2912Xu H., Wang W., Li C., Yu H., Yang A., Wang B., Jin Y. 2009. WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells. Cell Res. V. 19. P. 561. https://doi.org/10.1038/cr.2009.31Yadav D., Lee J.Y., Puranik N., Chauhan P.S., Chavda V., Jin J.-O., Lee P.C. 2022. Modulating the ubiquitin–proteasome system: a therapeutic strategy for autoimmune diseases. Cells. V. 11. P. 1093. https://doi.org/10.3390/cells11071093Yao T., Cohen R.E. 2002. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature. V. 419. P. 403. https://doi.org/10.1038/nature01071Young L.E., Fernandes K., McEvoy T.G., Butterwith S.C., Gutierrez C.G., Carolan C., Broadbent P.J., Robinson J.J., Wilmut I., Sinclair K.D. 2001. Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat. Genet. V. 27. P. 153. https://doi.org/10.1038/84769Young R.A. 2011. Control of the embryonic stem cell state. Cell. V. 144. P. 940. https://doi.org/10.1016/j.cell.2011.01.032Zhang F., Hu Y., Huang P., Toleman C.A., Paterson A.J., Kudlow J.E. 2007. Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. J. Biol. Chem. V. 282. P. 22460. https://doi.org/10.1074/jbc.M702439200Zhang F., Laiho M. 2003. On and off: proteasome and TGF-beta signaling. Exp. Cell Res. V. 291. P. 275. https://doi.org/10.1016/j.yexcr.2003.07.007Zhang X., Linder S., Bazzaro M. 2020. Drug development targeting the ubiquitin–proteasome system (UPS) for the treatment of human cancers. Cancers. V. 12. P. 902. https://doi.org/10.3390/cancers12040902Zhang Y., Ding H., Wang X., Wang X., Wan S., Xu A., Gan R., Ye S.-D. 2021. MK2 promotes Tfcp2l1 degradation via β-TrCP ubiquitin ligase to regulate mouse embryonic stem cell self-renewal. Cell Rep. V. 37. P. 109949. https://doi.org/10.1016/j.celrep.2021.109949Zhao S., Zhang C., Xu J., Liu S., Yu L., Chen S., Wen H., Li Z., Liu N. 2022. Dppa3 facilitates self-renewal of embryonic stem cells by stabilization of pluripotent factors. Stem Cell Res. Ther. V. 13. P. 169. https://doi.org/10.1186/s13287-022-02846-8Zhou L., Mideros S.X., Bao L., Hanlon R., Arredondo F.D., Tripathy S., Krampis K., Jerauld A., Evans C., St Martin S.K. 2009. Infection and genotype remodel the entire soybean transcriptome. BMC Genomics. V. 10. P. 49. https://doi.org/10.1186/1471-2164-10-49Zhou W., Zhu P., Wang J., Pascual G., Ohgi K.A., Lozach J., Glass C.K., Rosenfeld M.G. 2008. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. Mol. Cell. V. 29. P. 69. https://doi.org/10.1016/j.molcel.2007.11.002