Skip to main content
SpringerLink
Log in

Regulation of Treg Functions by the Ubiquitin Pathway

  • Chapter
  • First Online:
T Regulatory Cells in Human Health and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1278))

Abstract

Regulatory T (Tregs) cells, required to maintain immune homeostasis, have significant power in disease outcomes. Treg dysfunction, predominantly characterized by the loss of the master transcription factor FoxP3 and the acquisition of Teff-like phenotypes, can promote autoimmunity as well as enhance anti-tumor immunity. As FoxP3 expression and stability are pinnacle for Treg suppressive functions, understanding the pathways that regulate FoxP3 is crucial to ascertain Treg-mediated therapies for autoimmune diseases and cancer. Mechanisms controlling FoxP3 expression and stability range from transcriptional to posttranslational, revealing multiple therapeutic opportunities. While many of the transcriptional pathways have been explored in detail, a recent surge in interest on the posttranslational mechanisms regulating FoxP3 has arisen. Particularly, the role of ubiquitination on Tregs both directly and indirectly involving FoxP3 has gained interest. Here, we summarize the current knowledge on ubiquitin-dependent, FoxP3-mediated control of Treg function as it pertains to human diseases.

Deyu Fang is a Lead Contact.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Akimova T, Zhang T, Negorev D, Singhal S, Stadanlick J, Rao A, Annunziata M et al (2017) Human lung tumor FOXP+ Tregs upregulate four ‘Treg-locking’ transcription factors. JCI Insight 2(16):e94075

    Article  PubMed Central  Google Scholar 

  • Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M et al (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308(5719):248–251

    Article  CAS  PubMed  Google Scholar 

  • Amano T, Yamasaki S, Yagishita N, Tsuchimochi K, Shin H, Kawahara K, Aratani S et al (2003) Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev 17(19):2436–2449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H et al (2003) GRAIL an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18(4):535–547

    Article  CAS  PubMed  Google Scholar 

  • Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z et al (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293.e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bachmaier K, Krawczyk C, Kozieradzki I, Kong Y-Y, Sasaki T, Oliveira-dos-Santos A, Mariathasan S et al (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403(6766):211–216

    Article  CAS  PubMed  Google Scholar 

  • Bai Y, Yang C, Hu K, Elly C, Liu Y-C (2004) Itch E3 ligase-mediated regulation of TGF-β signaling by modulating Smad2 phosphorylation. Mol Cell 15(5):825–831

    Article  CAS  PubMed  Google Scholar 

  • Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin L-Y, Patterson C (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19(6):4535–4545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238

    Article  CAS  PubMed  Google Scholar 

  • BIRAC Consortium, Year Consortium, Raychaudhuri S, Thomson BP, Remmers EF, Eyre S, Hinks A et al (2009) Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat Genet 41(12):1313–1318

    Article  PubMed Central  CAS  Google Scholar 

  • Cejas PJ, Walsh MC, Pearce EL, Han D, Harms GM, Artis D, Turka LA et al (2010) TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 115(23):4750–4757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang J-H, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X et al (2012) Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13(5):481–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan D, Tian Z, Nicholson B, Kumar KGS, Zhou B, Carrasco R, McDermott JL et al (2012) A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22(3):345–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Barbi J, Bu S, Yang H-Y, Li Z, Gao Y, Jinasena D et al (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39(2):272–285

    Article  CAS  PubMed  Google Scholar 

  • Chen T, Hou X, Ni Y, Du W, Han H, Yu Y, Shi G (2018) The imbalance of FOXP3/GATA3 in regulatory T cells from the peripheral blood of asthmatic patients. J Immunol Res 2018:1–10

    Google Scholar 

  • Chernikova SB, Razorenova OV, Higgins JP, Sishc BJ, Nicolau M, Dorth JA, Chernikova DA et al (2012) Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability. Cancer Res 72(8):2111–2119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu R-J, Jang IK et al (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403(6766):216–220

    Article  CAS  PubMed  Google Scholar 

  • Chiffoleau E, Kobayashi T, Walsh MC, King CG, Walsh PT, Hancock WW, Choi Y et al (2003) TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease. J Immunol 171(11):5751–5759

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A, Elias S, Heller H, Hershko A (1982) ‘Covalent affinity’ purification of ubiquitin-activating enzyme. J Biol Chem 257(5):2537–2542

    Article  CAS  PubMed  Google Scholar 

  • Ciehanover A, Hod Y, Hershko A (1978) A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun 81(4):1100–1105

    Article  CAS  PubMed  Google Scholar 

  • Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67(19):9518–9527

    Article  CAS  PubMed  Google Scholar 

  • Cortez JT, Montauti E, Shifrut E, Gatchalian J, Zhang Y, Shaked O, Xu Y et al (2020) CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 582(7812):416–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cyr DM, Höhfeld J, Patterson C (2002) Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem Sci 27(7):368–375

    Article  CAS  PubMed  Google Scholar 

  • Dang EV, Barbi J, Yang H-Y, Jinasena D, Yu H, Zheng Y, Bordman Z et al (2011) Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146(5):772–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJP et al (2016) Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45(5):1135–1147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • DeWan AT, Egan KB, Hellenbrand K, Sorrentino K, Pizzoferrato N, Walsh KM, Bracken MB (2012) Whole-exome sequencing of a pedigree segregating asthma. BMC Med Genet 13(1):95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doníz-Padilla L, Martínez-Jiménez V, Niño-Moreno P, Abud-Mendoza C, Hernández-Castro B, González-Amaro R, Layseca-Espinosa E et al (2011) Expression and function of Cbl-b in T cells from patients with systemic lupus erythematosus, and detection of the 2126 A/G Cblb gene polymorphism in the Mexican mestizo population. Lupus 20(6):628–635

    Article  PubMed  Google Scholar 

  • Egawa S, Iijima H, Shinzaki S, Nakajima S, Wang J, Kondo J, Ishii S et al (2008) Upregulation of GRAIL is associated with remission of ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 295(1):G163–G169

    Article  CAS  PubMed  Google Scholar 

  • Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, Gimotty PA et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475(7355):226–230

    Article  CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    Article  CAS  PubMed  Google Scholar 

  • Fraile JM, Quesada V, Rodríguez D, Freije JMP, López-Otín C (2011) Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31(19):2373–2388

    Article  PubMed  CAS  Google Scholar 

  • Fukushima T, Matsuzawa S-i, Kress CL, Bruey JM, Krajewska M, Lefebvre S, Zapata JM et al (2007) Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses. Proc Natl Acad Sci 104(15):6371–6376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Tang J, Chen W, Li Q, Nie J, Lin F, Wu Q et al (2015) Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci 112(25):E3246–E3254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerondakis S, Banerjee A, Grigoriadis G, Vasanthakumar A, Gugasyan R, Sidwell T, Grumont RJ (2012) NF-κB subunit specificity in hemopoiesis. Immunol Rev 246(1):272–285

    Article  PubMed  CAS  Google Scholar 

  • Glinsky GV (2006) Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated PcG protein chromatin silencing pathway. Cell Cycle 5(11):1208–1216

    Article  CAS  PubMed  Google Scholar 

  • Glinsky GV, Berezovska O, Glinskii AB (2005) Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Investig 115(6):1503–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong L, Kamitani T, Millas S, Yeh ETH (2000) Identification of a novel isopeptidase with dual specificity for ubiquitin- and NEDD8-conjugated proteins. J Biol Chem 275(19):14212–14216

    Article  CAS  PubMed  Google Scholar 

  • Guan S-Y, Leng R-X, Tao J-H, Li X-P, Ye D-Q, Olsen N, Zheng SG, Pan H-F (2017) Hypoxia-inducible factor-1α: a promising therapeutic target for autoimmune diseases. Expert Opin Ther Targets 21(7):715–723

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Zhao M, Lu Q (2016) Transcription factor RFX1 is ubiquitinated by E3 ligase STUB1 in systemic lupus erythematosus. Clin Immunol 169:1–7

    Article  CAS  PubMed  Google Scholar 

  • Hahn MA, Dickson K-A, Jackson S, Clarkson A, Gill AJ, Marsh DJ (2012) The tumor suppressor CDC73 interacts with the ring finger proteins RNF20 and RNF40 and is required for the maintenance of histone 2B monoubiquitination. Hum Mol Genet 21(3):559–568

    Article  CAS  PubMed  Google Scholar 

  • Hanna J, Leggett DS, Finley D (2003) Ubiquitin depletion as a key mediator of toxicity by translational inhibitors. Mol Cell Biol 23(24):9251–9261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada Y, Harada Y, Elly C, Ying G, Paik J-H, DePinho RA, Liu Y-C (2010) Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med 207(7):1381–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holtzman MJ, Byers DE, Alexander-Brett J, Wang X (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14(10):686–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, Yoshioka Y et al (2017) Expression of vascular endothelial growth factor in ovarian cancer inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells. Clin Cancer Res 23(2):587–599

    Article  CAS  PubMed  Google Scholar 

  • Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-β–induced Foxp3+CD4+ CD25+ regulatory T cells are not mirror images of each other. Trends Immunol 29(9):429–435

    Article  CAS  PubMed  Google Scholar 

  • Hsiao H-W, Hsu T-S, Liu W-H, Hsieh W-C, Chou T-F, Wu Y-J, Jiang S-T et al (2015) Deltex1 antagonizes HIF-1α and sustains the stability of regulatory T cells in vivo. Nat Commun 6(1):6353

    Article  CAS  PubMed  Google Scholar 

  • Isomura I, Palmer S, Grumont RJ, Bunting K, Hoyne G, Wilkinson N, Banerjee A et al (2009) c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 206(13):3001–3014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ivashkiv LB (2020) The hypoxia–lactate axis tempers inflammation. Nat Rev Immunol 20:85–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang S, Song C, Gu X, Wang M, Miao D, Lv J, Liu Y (2018) Ubiquitin-specific peptidase 22 contributes to colorectal cancer stemness and chemoresistance via Wnt/β-catenin pathway. Cell Physiol Biochem 46(4):1412–1422

    Article  CAS  PubMed  Google Scholar 

  • Jin H, Park Y, Elly C, Liu Y-C (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Investig 123(11):4923–4934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson ES, Ma PCM, Ota IM, Varshavsky A (1995) A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 270(29):17442–17456

    Article  CAS  PubMed  Google Scholar 

  • Kerdiles YM, Stone EL, Beisner DL, McGargill MA, Ch’en IL, Stockmann C, Katayama CD et al (2010) Foxo transcription factors control regulatory T cell development and function. Immunity 33(6):890–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HT, Kim KP, Lledias F, Kisselev AF, Scaglione KM, Skowyra D, Gygi SP et al (2007) Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem 282(24):17375–17386

    Article  CAS  PubMed  Google Scholar 

  • Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S et al (2006) A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 25(20):4877–4887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi T, Walsh PT, Walsh MC, Speirs KM, Chiffoleau E, King CG, Hancock WW et al (2003) TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19(3):353–363

    Article  CAS  PubMed  Google Scholar 

  • Kong N, Lan Q, Chen M, Zheng T, Su W, Wang J, Yang Z et al (2012) Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells. Ann Rheum Dis 71(9):1567–1572

    Article  PubMed  Google Scholar 

  • Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, Lin A et al (2014) SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 15(4):431–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Lu Y, Wang S, Han Z, Zhu F, Ni Y, Liang R et al (2016) USP21 prevents the generation of T-helper-1-like Treg cells. Nat Commun 7(1):13559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Z, Yang H, Kong Q, Li J, Lee S-M, Gao B, Dong H et al (2012) USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Mol Cell 46(4):484–494

    Article  CAS  PubMed  Google Scholar 

  • Lin Z, Tan C, Qiu Q, Kong S, Yang H, Zhao F, Liu Z et al (2015) Ubiquitin-specific protease 22 is a deubiquitinase of CCNB1. Cell Discov 1(1):15028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liston A, Lu L-F, O’Carroll D, Tarakhovsky A, Rudensky AY (2008) Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 205(9):1993–2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL et al (2010) Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet 86(3):447–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q, Wang J et al (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci 111(33):E3432–E3440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv L, Xiao X, Gu Z, Zeng F, Huang L, Jiang G (2011) Silencing USP22 by asymmetric structure of interfering RNA inhibits proliferation and induces cell cycle arrest in bladder cancer cells. Mol Cell Biochem 346(1–2):11–21

    Article  CAS  PubMed  Google Scholar 

  • MacKenzie DA, Schartner J, Lin J, Timmel A, Jennens-Clough M, Fathman CG, Seroogy CM (2007) GRAIL is up-regulated in CD4 + CD25 + T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. J Biol Chem 282(13):9696–9702

    Article  CAS  PubMed  Google Scholar 

  • Mahajan D, Wang Y, Qin X, Wang Y, Zheng G, Wang YM, Alexander SI et al (2006) CD4+CD25+ regulatory T cells protect against injury in an innate murine model of chronic kidney disease. J Am Soc Nephrol 17(10):2731–2741

    Article  CAS  PubMed  Google Scholar 

  • Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F (2003) CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 197(1):111–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao F, Kong H, Zhao Y, Peng L, Chen W, Zhang J, Cheng P et al (2017) Increased tumor-infiltrating CD45RA−CCR7− regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress. Cell Death Dis 8(8):e3002–e3002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinon F, Chen X, Lee A-H, Glimcher LH (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11(5):411–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muto G, Kotani H, Kondo T, Morita R, Tsuruta S, Kobayashi T, Luche H et al (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. PLoS One 8(9):e74639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Namjou B, Choi C-B, Harley ITW, Alarcón-Riquelme ME, Network B, Kelly JA, Glenn SB et al (2012) Evaluation of TRAF6 in a large multiancestral lupus cohort. Arthritis Rheum 64(6):1960–1969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni X, Kou W, Gu J, Wei P, Wu X, Peng H, Tao J et al (2019) TRAF 6 directs FOXP 3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination. EMBO J 38(9):e99766, available at: https://doi.org/10.15252/embj.201899766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nicholson B, Kumar KGS (2011) The multifaceted roles of USP7: new therapeutic opportunities. Cell Biochem Biophys 60(1–2):61

    Article  CAS  PubMed  Google Scholar 

  • Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM et al (2010) The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32(5):670–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J et al (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21(8):921–926

    Article  CAS  PubMed  Google Scholar 

  • Piao S, Liu Y, Hu J, Guo F, Ma J, Sun Y, Zhang B (2012) USP22 is useful as a novel molecular marker for predicting disease progression and patient prognosis of oral squamous cell carcinoma. PLoS One 7(8):e42540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM et al (2016) Regulatory T cells exhibit distinct features in human breast cancer. Immunity 45(5):1122–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prenzel T, Begus-Nahrmann Y, Kramer F, Hennion M, Hsu C, Gorsler T, Hintermair C et al (2011) Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasome-dependent monoubiquitination of histone H2B. Cancer Res 71(17):5739–5753

    Article  CAS  PubMed  Google Scholar 

  • Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ, Colligon TA et al (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4(134):134ra62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G (2015) Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep 11(4):577–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robb R, Munck A, Smith K (1981) T cell growth factor receptors. Quantitation, specificity, and biological relevance. J Exp Med 154(5):1455–1474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164

    Article  CAS  PubMed  Google Scholar 

  • Sanna S, Pitzalis M, Zoledziewska M, Zara I, Sidore C, Murru R, Whalen MB et al (2010) Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Nat Genet 42(6):495–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, Callahan DJ et al (2019) Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol 20(6):724–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaer DA, Budhu S, Liu C, Bryson C, Malandro N, Cohen A, Zhong H et al (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T-cell lineage stability. Cancer Immunol Res 1(5):320–331

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Supprian M, Tian J, Grant EP, Pasparakis M, Maehr R, Ovaa H, Ploegh HL et al (2004) Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc Natl Acad Sci U S A 101(13):4566–4571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shema E, Tirosh I, Aylon Y, Huang J, Ye C, Moskovits N, Raver-Shapira N et al (2008) The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes Dev 22(19):2664–2676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimo Y, Yanai H, Ohshima D, Qin J, Motegi H, Maruyama Y, Hori S et al (2011) TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells 16(4):437–447

    Article  CAS  PubMed  Google Scholar 

  • Singh B, Read S, Asseman C, Malmström V, Mottet C, Stephens LA, Stepankova R et al (2001) Control of intestinal inflammation by regulatory T cells. Immunol Rev 182(1):190–200

    Article  CAS  PubMed  Google Scholar 

  • Suresh B, Lee J, Kim H, Ramakrishna S (2016) Regulation of pluripotency and differentiation by deubiquitinating enzymes. Cell Death Differ 23(8):1257–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6(2):152–162

    Article  CAS  PubMed  Google Scholar 

  • Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, Morita R et al (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production. J Exp Med 208(10):2055–2067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX et al (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4 + CD25 + regulatory T cells. J Immunol 171(7):3348–3352

    Article  CAS  PubMed  Google Scholar 

  • Tarcic O, Pateras IS, Cooks T, Shema E, Kanterman J, Ashkenazi H, Boocholez H et al (2016) RNF20 links histone H2B ubiquitylation with inflammation and inflammation-associated cancer. Cell Rep 14(6):1462–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tenno T, Fujiwara K, Tochio H, Iwai K, Morita EH, Hayashi H, Murata S et al (2004) Structural basis for distinct roles of Lys63- and Lys48-linked polyubiquitin chains. Genes Cells 9(10):865–875

    Article  CAS  PubMed  Google Scholar 

  • van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, Beekman JM, van Beekum O, Brenkman AB et al (2009) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115(5):965–974

    Article  PubMed  CAS  Google Scholar 

  • van Loosdregt J, Brunen D, Fleskens V, Pals CEGM, Lam EWF, Coffer PJ (2011) Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One 6(4):e19047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CPJ, Pals CEGM, Meerding J et al (2013) Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39(2):259–271

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, Su J et al (2008) The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 9(3):245–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vignali DAA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8(7):523–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35(3):337–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang G, Gao Y, Li L, Jin G, Cai Z, Chao J-I, Lin H-K (2012) K63-linked ubiquitination in kinase activation and cancer. Front Oncol 2:5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z-J, Yang J-L, Wang Y-P, Lou J-Y, Chen J, Liu C, Guo L-D (2013) Decreased histone H2B monoubiquitination in malignant gastric carcinoma. World J Gastroenterol 19(44):8099–8107

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang L, Kumar S, Dahiya S, Wang F, Wu J, Newick K, Han R et al (2016) Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 13:99–112

    Article  PubMed  PubMed Central  Google Scholar 

  • Wei Q, Sha Y, Bhattacharya A, Fattah EA, Bonilla D, Jyothula SSSK, Pandit L et al (2013) Regulation of IL-4 receptor signaling by STUB1 in lung inflammation. Am J Respir Crit Care Med 189(1):16–29

    Article  Google Scholar 

  • Westendorf AM, Skibbe K, Adamczyk A, Buer J, Geffers R, Hansen W, Pastille E et al (2017) Hypoxia enhances immunosuppression by inhibiting CD4+ effector T cell function and promoting Treg activity. Cell Physiol Biochem 41(4):1271–1284

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson KD (1997) Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J 11(14):1245–1256

    Article  CAS  PubMed  Google Scholar 

  • Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA et al (2011) GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Investig 121(11):4503–4515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC et al (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61(12):4766–4772

    CAS  PubMed  Google Scholar 

  • Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y, Robert J, Rush J et al (2009) Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137(1):133–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Zhao F, Qiu Q, Chen K, Wei J, Kong Q, Gao B et al (2016) The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat Commun 7(1):12073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Melo-Cardenas J, Zhang Y, Gau I, Wei J, Montauti E, Zhang Y et al (2019) The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress response. JCI Insight 4(5):e121887

    Article  PubMed Central  Google Scholar 

  • Yu Y, Su Z, Wang Z, Xu H (2017) USP7 is associated with greater disease activity in systemic lupus erythematosus via stabilization of the IFNα receptor. Mol Med Rep 16(2):2274–2280

    Article  CAS  PubMed  Google Scholar 

  • Zhang X-Y, Varthi M, Sykes SM, Phillips C, Warzecha C, Zhu W, Wyce A et al (2008) The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Mol Cell 29(1):102–111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang J, Chen C, Hou X, Gao Y, Lin F, Yang J, Gao Z et al (2013) Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3. J Biol Chem 288(13):9373–9382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Chen Z, Luo X, Wu B, Li B, Wang B (2016) Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Hum Vaccin Immunother 12(10):2512–2518

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Guo H, Qiao G, Zucker M, Langdon WY, Zhang J (2015) E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4+CD25+ regulatory T cell development by targeting Foxp3 for ubiquitination. J Immunol 194(4):1639–1645

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA (2002) Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25− precursors. J Immunol 169(8):4183–4189

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25− cells to develop suppressive activity: the role of IL-2, TGF-β, and IL-10. J Immunol 172(9):5213–5221

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA (2006) TGF-β requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321–3329

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang J, Horwitz DA (2008) Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-β are resistant to Th17 conversion by IL-6. J Immunol 180(11):7112–7116

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT, Bluestone JA (2008) Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med 205(9):1983–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Kong N, Wang J, Fan H, Zou H, Horwitz D, Brand D et al (2010) Cutting edge: all-trans retinoic acid sustains the stability and function of natural regulatory T cells in an inflammatory milieu. J Immunol 185(5):2675–2679

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the NIH grant DK120330 and CA232347 to DF, as well as F31 CA220801-03 to EM.

Author information

Authors and Affiliations

  1. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Elena Montauti & Deyu Fang

Authors
  1. Elena Montauti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deyu Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deyu Fang .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA

    Song-Guo Zheng

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Montauti, E., Fang, D. (2021). Regulation of Treg Functions by the Ubiquitin Pathway. In: Zheng, SG. (eds) T Regulatory Cells in Human Health and Diseases. Advances in Experimental Medicine and Biology, vol 1278. Springer, Singapore. https://doi.org/10.1007/978-981-15-6407-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation