Volume 10 Issue 6
Jun.  2019
Turn off MathJax
Article Contents
Daisuke Aki, Qian Li, Hui Li, Yun-Cai Liu, Jee Ho Lee. Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch[J]. Protein&Cell, 2019, 10(6): 395-404. doi: 10.1007/s13238-018-0586-8
Citation: Daisuke Aki, Qian Li, Hui Li, Yun-Cai Liu, Jee Ho Lee. Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch[J]. Protein&Cell, 2019, 10(6): 395-404. doi: 10.1007/s13238-018-0586-8

Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch

doi: 10.1007/s13238-018-0586-8

This work is supported by funding from MOST YFA0505802, NSFC81630041, NIH RO1AI123398 and R21AI122258.

  • Received Date: 2018-09-26
  • Protein ubiquitination is an important means of posttranslational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4+ T helper cell subsets, the stability of regulatory T cells, effector function of CD8+ T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.
  • loading
  • [1]
    Abbott RK, Thayer M, Labuda J, Silva M, Philbrook P, Cain DW, Kojima H, Hatfield S, Sethumadhavan S, Ohta A et al (2016) Germinal center hypoxia potentiates immunoglobulin class switch recombination. J Immunol 197:4014-4020
    Aki D, Li H, Zhang W, Zheng M, Elly C, Lee JH, Zou W, Liu YC (2018) The E3 ligases Itch and WWP2 cooperate to limit TH2 differentiation by enhancing signaling through the TCR. Nat Immunol. 19:766-775
    Aki D, Zhang W, Liu YC (2015) The E3 ligase itch in immune regulation and beyond. Immunol Rev 266:6-26
    Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A et al (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403:211-216
    Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38:2412-2418
    Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH (2004) Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol 24:9038-9047
    Brigui A, Hofmann L, Arguelles C, Sanial M, Holmgren RA, Plessis A (2015) Control of the dynamics and homeostasis of the Drosophila Hedgehog receptor Patched by two C2-WW-HECTE3 Ubiquitin ligases. Open Biol 5:150112
    Chaudhary N, Maddika S (2014) WWP2-WWP1 ubiquitin ligase complex coordinated by PPM1G maintains the balance between cellular p73 and DeltaNp73 levels. Mol Cell Biol 34:3754-3764
    Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X, Devreotes P, Wolberger C, Amzel LM, Gabelli SB et al (2017) A tunable brake for HECT ubiquitin ligases. Mol Cell 66(345-357):e346
    Chen Z, Thomas SN, Bolduc DM, Jiang X, Zhang X, Wolberger C, Cole PA (2016) Enzymatic analysis of PTEN ubiquitylation by WWP2 and NEDD4-1 E3 ligases. Biochemistry 55:3658-3666
    Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403:216-220
    Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, Thomas JW, Hiebert S, Haase VH, Boothby MR (2016) Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537:234-238
    Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 109:E2784-2793
    Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH et al (2016) Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166(1117-1131):e1114
    Constantinides MG, McDonald BD, Verhoef PA, Bendelac A (2014) A committed precursor to innate lymphoid cells. Nature 508:397-401
    Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya Tet al (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439-2453
    Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146:772-784
    Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW (2013) Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14:1173-1182
    Ebbo M, Crinier A, Vely F, Vivier E (2017) Innate lymphoid cells:major players in inflammatory diseases. Nat Rev Immunol 17:665-678
    Eliasson P, Jonsson JI (2010) The hematopoietic stem cell niche:low in oxygen but a nice place to be. J Cell Physiol 222:17-22
    Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, Mauri C (2007) Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 178:7868-7878
    Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, Hunter T, Copeland N, Jenkins N, Liu YC (2002) Dysregulation of T lymphocyte function in itchy mice:a role for Itch in TH2 differentiation. Nat Immunol 3:281-287
    Gilberto S, Peter M (2017) Dynamic ubiquitin signaling in cell cycle regulation. J Cell Biol 216:2259-2271
    Hale LP, Braun RD, Gwinn WM, Greer PK, Dewhirst MW (2002) Hypoxia in the thymus:role of oxygen tension in thymocyte survival. Am J Physiol Heart Circ Physiol 282:H1467-1477
    Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5:255-265
    Huang H, Jeon MS, Liao L, Yang C, Elly C, Yates JR 3rd, Liu YC (2010) K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity 33:60-70
    Hustad CM, Perry WL, Siracusa LD, Rasberry C, Cobb L, Cattanach BM, Kovatch R, Copeland NG, Jenkins NA (1995) Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics 140:255-265
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHLmediated destruction by proline hydroxylation:implications for O2 sensing. Science 292:464-468
    Izquierdo HM, Brandi P, Gomez MJ, Conde-Garrosa R, Priego E, Enamorado M, Martinez-Cano S, Sanchez I, Conejero L, Jimenez-Carretero D et al (2018) Von hippel-lindau protein is required for optimal alveolar macrophage terminal differentiation, self-renewal, and function. Cell Rep 24:1738-1746
    Jellusova J, Cato MH, Apgar JR, Ramezani-Rad P, Leung CR, Chen C, Richardson AD, Conner EM, Benschop RJ, Woodgett JR et al(2017) Gsk3 is a metabolic checkpoint regulator in B cells. Nat Immunol 18:303-312
    Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L et al (2004) Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21:167-177
    Jiang J, Wang N, Jiang Y, Tan H, Zheng J, Chen G, Jia Z (2015) Characterization of substrate binding of the WW domains in human WWP2 protein. FEBS Lett 589:1935-1942
    Jin HS, Park Y, Elly C, Liu YC (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123:4923-4934
    Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC (1999) The tyrosine kinase negative regulator c-Cbl as a RINGtype, E2-dependent ubiquitin-protein ligase. Science 286:309-312
    Kaelin WG Jr, Maher ER (1998) The VHL tumour-suppressor gene paradigm. Trends Genet 14:423-426
    Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor 1alpha:posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA 94:5667-5672
    Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG Jr, Elledge SJ, Conaway RC et al (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284:657-661
    Kathania M, Khare P, Zeng M, Cantarel B, Zhang H, Ueno H, Venuprasad K (2016) Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-gammat ubiquitination. Nat Immunol 17:997-1004
    Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991-5004
    Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T, Carmeliet P, Semenza GL, Sitkovsky MV (2002) Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci USA 99:2170-2174
    Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37:937-953
    Layman AAK, Sprout SL, Phillips D, Oliver PM (2017) Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production. Sci Rep 7:39649
    Lee JH, Elly C, Park Y, Liu YC (2015) E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1alpha to maintain regulatory T Cell stability and suppressive capacity. Immunity 42:1062-1074
    Li Q, Li D, Zhang X, Wan Q, Zhang W, Zheng M, Zou L, Elly C, Lee JH, Liu YC (2018) E3 ligase VHL promotes group 2 innate lymphoid cell maturation and function via glycolysis inhibition and induction of interleukin-33 receptor. Immunity 48(258-270):e255
    Liu YC (2004) Ubiquitin ligases and the immune response. Annu Rev Immunol 22:81-127
    Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL, Chikwava KR, Cummings OW, Morton DH et al (2010) Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet 86:447-453
    Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM (1999) RING fingers mediate ubiquitin-conjugating enzyme(E2)-dependent ubiquitination. Proc Natl Acad Sci USA 96:11364-11369
    Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, Kallies A, Nutt SL, Sakaguchi S, Takeda K et al (2014) Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 41:1040-1051
    Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118:3420-3430
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxiainducible factors for oxygen-dependent proteolysis. Nature 399:271-275
    Meng X, Grotsch B, Luo Y, Knaup KX, Wiesener MS, Chen XX, Jantsch J, Fillatreau S, Schett G, Bozec A (2018) Hypoxiainducible factor-1alpha is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat Commun 9:251
    Metzger MB, Hristova VA, Weissman AM (2012) HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci 125:531-537
    Nakashima H, Hamaguchi Y, Watanabe R, Ishiura N, Kuwano Y, Okochi H, Takahashi Y, Tamaki K, Sato S, Tedder TF et al (2010) CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions. J Immunol 184:4637-4645
    Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH, Freedman BD, Turka LA (2005) Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci USA 102:17071-17076
    O'Connor HF, Lyon N, Leung JW, Agarwal P, Swaim CD, Miller KM, Huibregtse JM (2015) Ubiquitin-Activated Interaction Traps(UBAITs) identify E3 ligase binding partners. EMBO Rep 16:1699-1712
    Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C et al(2017) Interferon-gamma drives treg fragility to promote antitumor immunity. Cell 169(1130-1141):e1111
    Palazon A, Goldrath AW, Nizet V, Johnson RS (2014) HIF transcription factors, inflammation, and immunity. Immunity 41:518-528
    Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 18:143-146
    Phan AT, Doedens AL, Palazon A, Tyrakis PA, Cheung KP, Johnson RS, Goldrath AW (2016) Constitutive glycolytic metabolism supports CD8(+) T cell effector memory differentiation during viral infection. Immunity 45:1024-1037
    Riling C, Kamadurai H, Kumar S, O'Leary CE, Wu KP, Manion EE, Ying M, Schulman BA, Oliver PM (2015) Itch WW domains inhibit its E3 ubiquitin ligase activity by blocking E2-E3 ligase transthiolation. J Biol Chem 290:23875-23887
    Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453:807-811
    Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367-1376
    Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE et al (2013) Innate lymphoid cells-a proposal for uniform nomenclature. Nat Rev Immunol 13:145-149
    Stebbins CE, Kaelin WG Jr, Pavletich NP (1999) Structure of the VHL-ElonginC-ElonginB complex:implications for VHL tumor suppressor function. Science 284:455-461
    Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY, Emslie E, Lin YC, Yang E, Goldrath AW, Li MO et al (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42:239-251
    Venuprasad K, Elly C, Gao M, Salek-Ardakani S, Harada Y, Luo JL, Yang C, Croft M, Inoue K, Karin M et al (2006) Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest 116:1117-1126
    Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, Su J, Liu YC (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 9:245-253
    Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201:105-115
    Xiao N, Eto D, Elly C, Peng G, Crotty S, Liu YC (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15:657-666
    Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:407-420
    Zhu K, Shan Z, Chen X, Cai Y, Cui L, Yao W, Wang Z, Shi P, Tian C, Lou J et al (2017) Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch. EMBO Rep 18:1618-1630
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (798) PDF downloads(97) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint