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A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks

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Abstract

Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligase-dependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review.

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References

  1. Reinstein E, Ciechanover A (2006) Narrative review: protein degradation and human diseases: the ubiquitin connection. Ann Intern Med 145:676–684

    Article  PubMed  Google Scholar 

  2. Dahlmann B (2007) Role of proteasomes in disease. BMC Biochem 8(Suppl 1):S3

    Article  PubMed  Google Scholar 

  3. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    Article  PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. Schulman BA, Harper JW (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 10:319–331

    Article  PubMed  CAS  Google Scholar 

  6. Hatakeyama S, Nakayama KI (2003) U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun 302:635–645

    Article  PubMed  CAS  Google Scholar 

  7. Deshaies RJ, Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78:399–434

    Article  PubMed  CAS  Google Scholar 

  8. Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10:398–409

    Article  PubMed  CAS  Google Scholar 

  9. Marin I (2010) Animal HECT ubiquitin ligases: evolution and functional implications. BMC Evol Biol 10:56

    Article  PubMed  Google Scholar 

  10. Wan L, Zou W, Gao D et al (2011) Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1. Mol Cell 44:721–733

    Article  PubMed  CAS  Google Scholar 

  11. Aragon E, Goerner N, Zaromytidou AI et al (2011) A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25:1275–1288

    Article  PubMed  CAS  Google Scholar 

  12. Tian M, Bai C, Lin Q et al (2011) Binding of RhoA by the C2 domain of E3 ligase Smurf1 is essential for Smurf1-regulated RhoA ubiquitination and cell protrusive activity. FEBS Lett 585:2199–2204

    Article  PubMed  CAS  Google Scholar 

  13. Yamaguchi K, Ohara O, Ando A, Nagase T (2008) Smurf1 directly targets hPEM-2, a GEF for Cdc42, via a novel combination of protein interaction modules in the ubiquitin-proteasome pathway. Biol Chem 389:405–413

    Article  PubMed  CAS  Google Scholar 

  14. Nie J, Liu L, Wu M et al (2010) HECT ubiquitin ligase Smurf1 targets the tumor suppressor ING2 for ubiquitination and degradation. FEBS Lett 584:3005–3012

    Article  PubMed  CAS  Google Scholar 

  15. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH (1999) A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400:687–693

    Article  PubMed  CAS  Google Scholar 

  16. Morén A, Imamura T, Miyazono K, Heldin CH, Moustakas A (2005) Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem 280:22115–22123

    Article  PubMed  Google Scholar 

  17. Suzuki C, Murakami G, Fukuchi M et al (2002) Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem 277:39919–39925

    Article  PubMed  CAS  Google Scholar 

  18. Ebisawa T, Fukuchi M, Murakami G et al (2001) Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276:12477–12480

    Article  PubMed  CAS  Google Scholar 

  19. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14:2809–2817

    Article  PubMed  CAS  Google Scholar 

  20. Grönroos E, Hellman U, Heldin CH, Ericsson J (2002) Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell 10:483–493

    Article  PubMed  Google Scholar 

  21. Lin X, Liang M, Feng XH (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 275:36818–36822

    Article  PubMed  CAS  Google Scholar 

  22. Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98:974–979

    Article  PubMed  CAS  Google Scholar 

  23. Kuratomi G, Komuro A, Goto K et al (2005) NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4–2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J 386:461–470

    Article  PubMed  CAS  Google Scholar 

  24. Kavsak P, Rasmussen RK, Causing CG et al (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6:1365–1375

    Article  PubMed  CAS  Google Scholar 

  25. Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939–27944

    Article  PubMed  CAS  Google Scholar 

  26. Shen R, Chen M, Wang YJ et al (2006) Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 281:3569–3576

    Article  PubMed  CAS  Google Scholar 

  27. Chen YL, Liu B, Zhou ZN et al (2009) Smad6 inhibits the transcriptional activity of Tbx6 by mediating its degradation. J Biol Chem 284:23481–23490

    Article  PubMed  CAS  Google Scholar 

  28. Yamashita M, Ying SX, Zhang GM et al (2005) Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121:101–113

    Article  PubMed  CAS  Google Scholar 

  29. Zhao L, Huang J, Guo R, Wang Y, Chen D, Xing L (2010) Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation. J Bone Miner Res 25:1246–1256

    Article  PubMed  CAS  Google Scholar 

  30. Kalkan T, Iwasaki Y, Park CY, Thomsen GH (2009) Tumor necrosis factor-receptor-associated factor-4 is a positive regulator of transforming growth factor-beta signaling that affects neural crest formation. Mol Biol Cell 20:3436–3450

    Article  PubMed  CAS  Google Scholar 

  31. Heissmeyer V, Rao A (2008) Itching to end NF-kappaB. Nat Immunol 9:227–229

    Article  PubMed  CAS  Google Scholar 

  32. Wang HR, Zhang Y, Ozdamar B et al (2003) Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302:1775–1779

    Article  PubMed  CAS  Google Scholar 

  33. Lu K, Li P, Zhang M et al (2011) Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection. J Biol Chem 286:16861–16870

    Article  PubMed  CAS  Google Scholar 

  34. Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307:1603–1609

    Article  PubMed  CAS  Google Scholar 

  35. Cheng PL, Lu H, Shelly M, Gao H, Poo MM (2011) Phosphorylation of E3 ligase Smurf1 switches its substrate preference in support of axon development. Neuron 69:231–243

    Article  PubMed  CAS  Google Scholar 

  36. Huang C, Rajfur Z, Yousefi N, Chen Z, Jacobson K, Ginsberg MH (2009) Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nat Cell Biol 11:624–630

    Article  PubMed  CAS  Google Scholar 

  37. Narimatsu M, Bose R, Pye M et al (2009) Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell 137:295–307

    Article  PubMed  CAS  Google Scholar 

  38. Li S, Lu K, Wang J et al (2010) Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem 338:11–17

    Article  PubMed  CAS  Google Scholar 

  39. Inoue J, Ishida T, Tsukamoto N et al (2000) Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res 254:14–24

    Article  PubMed  CAS  Google Scholar 

  40. Wu H, Arron JR (2003) TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays 25:1096–1105

    Article  PubMed  CAS  Google Scholar 

  41. Lee YS, Park JS, Kim JH et al (2011) Smad6-specific recruitment of Smurf E3 ligases mediates TGF-beta1-induced degradation of MyD88 in TLR4 signalling. Nat Commun 2:460

    Article  PubMed  Google Scholar 

  42. Yuan C, Qi J, Zhao X, Gao C (2012) Smurf1 protein negatively regulates interferon-gamma signaling through promoting STAT1 protein ubiquitination and degradation. J Biol Chem 287:17006–17015

    Article  PubMed  CAS  Google Scholar 

  43. Xie P, Tang Y, Shen S et al (2011) Smurf1 ubiquitin ligase targets Kruppel-like factor KLF2 for ubiquitination and degradation in human lung cancer H1299 cells. Biochem Biophys Res Commun 407:254–259

    Article  PubMed  CAS  Google Scholar 

  44. Guo X, Shen S, Song S et al (2011) The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. J Biol Chem 286:18037–18047

    Article  PubMed  CAS  Google Scholar 

  45. Nie J, Xie P, Liu L et al (2010) Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by stabilizing the E3 ligase MDM2. J Biol Chem 285:22818–22830

    Article  PubMed  CAS  Google Scholar 

  46. Orvedahl A, Sumpter R Jr, Xiao G et al (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113–117

    Article  PubMed  CAS  Google Scholar 

  47. Lu K, Yin X, Weng T et al (2008) Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1. Nat Cell Biol 10:994–1002

    Article  PubMed  CAS  Google Scholar 

  48. Crose LE, Hilder TL, Sciaky N, Johnson GL (2009) Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells. J Biol Chem 284:13301–13305

    Article  PubMed  CAS  Google Scholar 

  49. Townsend TA, Wrana JL, Davis GE, Barnett JV (2008) Transforming growth factor-beta-stimulated endocardial cell transformation is dependent on Par6c regulation of RhoA. J Biol Chem 283:13834–13841

    Article  PubMed  CAS  Google Scholar 

  50. Wiesner S, Ogunjimi AA, Wang HR et al (2007) Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 130:651–662

    Article  PubMed  CAS  Google Scholar 

  51. Gallagher E, Gao M, Liu YC, Karin M (2006) Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc Natl Acad Sci USA 103:1717–1722

    Article  PubMed  CAS  Google Scholar 

  52. Ogunjimi AA, Briant DJ, Pece-Barbara N et al (2005) Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell 19:297–308

    Article  PubMed  CAS  Google Scholar 

  53. Sangadala S, Boden SD, Viggeswarapu M, Liu Y, Titus L (2006) LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads. J Biol Chem 281:17212–17219

    Article  PubMed  CAS  Google Scholar 

  54. Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P (2006) Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol 8:485–491

    Article  PubMed  CAS  Google Scholar 

  55. Koinuma D, Shinozaki M, Komuro A et al (2003) Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J 22:6458–6470

    Article  PubMed  CAS  Google Scholar 

  56. Choi SH, Seo GY, Nam EH et al (2007) Opposing effects of Arkadia and Smurf on TGFbeta1-induced IgA isotype expression. Mol Cells 24:283–287

    PubMed  CAS  Google Scholar 

  57. Yan X, Zhang J, Pan L et al (2011) TSC-22 promotes transforming growth factor beta-mediated cardiac myofibroblast differentiation by antagonizing Smad7 activity. Mol Cell Biol 31:3700–3709

    Article  PubMed  CAS  Google Scholar 

  58. Fukunaga E, Inoue Y, Komiya S et al (2008) Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J Biol Chem 283:35660–35667

    Article  PubMed  CAS  Google Scholar 

  59. Cui Y, He S, Xing C et al (2011) SCFFBXL15 regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1. EMBO J 30:2675–2689

    Article  PubMed  CAS  Google Scholar 

  60. Chan MC, Nguyen PH, Davis BN et al (2007) A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor. Mol Cell Biol 27:5776–5789

    Article  PubMed  CAS  Google Scholar 

  61. Kaneki H, Guo R, Chen D et al (2006) Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281:4326–4333

    Article  PubMed  CAS  Google Scholar 

  62. Guo R, Yamashita M, Zhang Q et al (2008) Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins. J Biol Chem 283:23084–23092

    Article  PubMed  CAS  Google Scholar 

  63. Liu Y, Liu W, Hu C et al (2011) MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis. Stem Cells 29:1804–1816

    Article  PubMed  CAS  Google Scholar 

  64. Murakami K, Mathew R, Huang J et al (2010) Smurf1 ubiquitin ligase causes downregulation of BMP receptors and is induced in monocrotaline and hypoxia models of pulmonary arterial hypertension. Exp Biol Med (Maywood) 235:805–813

    Article  CAS  Google Scholar 

  65. Panchenko MP, Siddiquee Z, Dombkowski DM et al (2010) Protein kinase CK1alphaLS promotes vascular cell proliferation and intimal hyperplasia. Am J Pathol 177:1562–1572

    Article  PubMed  CAS  Google Scholar 

  66. Horiki M, Imamura T, Okamoto M et al (2004) Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. J Cell Biol 165:433–445

    Article  PubMed  CAS  Google Scholar 

  67. Alexandrova EM, Thomsen GH (2006) Smurf1 regulates neural patterning and folding in Xenopus embryos by antagonizing the BMP/Smad1 pathway. Dev Biol 299:398–410

    Article  PubMed  CAS  Google Scholar 

  68. Podos SD, Hanson KK, Wang YC, Ferguson EL (2001) The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis. Dev Cell 1:567–578

    Article  PubMed  CAS  Google Scholar 

  69. Xia L, Jia S, Huang S et al (2010) The Fused/Smurf complex controls the fate of Drosophila germline stem cells by generating a gradient BMP response. Cell 143:978–990

    Article  PubMed  CAS  Google Scholar 

  70. Shi W, Chen H, Sun J et al (2004) Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. Am J Physiol Lung Cell Mol Physiol 286:L293–L300

    Article  PubMed  CAS  Google Scholar 

  71. Bernassola F, Karin M, Ciechanover A, Melino G (2008) The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14:10–21

    Article  PubMed  CAS  Google Scholar 

  72. Wang X, Trotman LC, Koppie T et al (2007) NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128:129–139

    Article  PubMed  CAS  Google Scholar 

  73. Laine A, Ronai Z (2007) Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26:1477–1483

    Article  PubMed  CAS  Google Scholar 

  74. Chen C, Zhou Z, Ross JS, Zhou W, Dong JT (2007) The amplified WWP1 gene is a potential molecular target in breast cancer. Int J Cancer 121:80–87

    Article  PubMed  CAS  Google Scholar 

  75. Sanchez NS, Barnett JV (2012) TGFbeta and BMP-2 regulate epicardial cell invasion via TGFbetaR3 activation of the Par6/Smurf1/RhoA pathway. Cell Signal 24:539–548

    Article  PubMed  CAS  Google Scholar 

  76. Sahai E, Garcia-Medina R, Pouyssegur J, Vial E (2007) Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J Cell Biol 176:35–42

    Article  PubMed  CAS  Google Scholar 

  77. Kwei KA, Shain AH, Bair R et al (2011) SMURF1 amplification promotes invasiveness in pancreatic cancer. PLoS One 6:e23924

    Article  PubMed  CAS  Google Scholar 

  78. Bashyam MD, Bair R, Kim YH et al (2005) Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia 7:556–562

    Article  PubMed  CAS  Google Scholar 

  79. Suzuki A, Shibata T, Shimada Y et al (2008) Identification of SMURF1 as a possible target for 7q21.3-22.1 amplification detected in a pancreatic cancer cell line by in-house array-based comparative genomic hybridization. Cancer Sci 99:986–994

    Article  PubMed  CAS  Google Scholar 

  80. van Dekken H, Tilanus HW, Hop WC et al (2009) Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction. Cancer Genet Cytogenet 189:37–42

    Article  PubMed  Google Scholar 

  81. Blank M, Tang Y, Yamashita M, Burkett SS, Cheng SY, Zhang YE (2012) A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nat Med 18:227–234

    Article  PubMed  CAS  Google Scholar 

  82. Bryan B, Cai Y, Wrighton K, Wu G, Feng XH, Liu M (2005) Ubiquitination of RhoA by Smurf1 promotes neurite outgrowth. FEBS Lett 579:1015–1019

    Article  PubMed  CAS  Google Scholar 

  83. Vohra BP, Fu M, Heuckeroth RO (2007) Protein kinase Czeta and glycogen synthase kinase-3beta control neuronal polarity in developing rodent enteric neurons, whereas SMAD specific E3 ubiquitin protein ligase 1 promotes neurite growth but does not influence polarity. J Neurosci 27:9458–9468

    Article  PubMed  CAS  Google Scholar 

  84. Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals. ‘protein modifications: beyond the usual suspects’ review series. EMBO Rep 9:536–542

    Article  PubMed  CAS  Google Scholar 

  85. Dikic I, Wakatsuki S, Walters KJ (2009) Ubiquitin-binding domains—from structures to functions. Nat Rev Mol Cell Biol 10:659–671

    Article  PubMed  CAS  Google Scholar 

  86. Hua Z, Vierstra RD (2011) The cullin-RING ubiquitin-protein ligases. Annu Rev Plant Biol 62:299–334

    Article  PubMed  CAS  Google Scholar 

  87. Mocciaro A, Rape M (2012) Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control. J Cell Sci 125:255–263

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank all the collaborators from Hong Kong, Beijing, and Tianjin for their kind support in scientific investigations, Shengbo Fu (New York University, USA) for his meticulous advice, and all the group members for their helpful suggestions. This work was supported by the grants from the National Basic Research Programs (2011CB910602, 2012CB910304), and the National Natural Science Foundation Projects (31125010, 30830029, 31000338).

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  1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China

    Yu Cao & Lingqiang Zhang

  2. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, Liaoning Province, China

    Lingqiang Zhang

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Appendices

Appendix 1 Ubiquitylation cascade and chain linkages

Ubiquitylation. A highly conserved 76 amino acid polypeptide, ubiquitin, can be initially activated by an E1 in an ATP-dependent process; with the active-site cysteine residue in E1 forms a high-energy thioester linkage with the carboxyl terminus of an Ub molecule. The activated Ub is then trans-thiolated from E1 to an active-site cysteine residue of one E2. Finally, Ub molecule is donated to a specific lysine residue (abbreviated as Lys or K) of a substrate through an E3-dependent manner (Fig. 1a). Ubiquitylation may occur once or multiple times, resulting in mono-ubiquitylation (attaching a single Ub molecule at a lysine residue), multi-ubiquitylation (attaching a single Ub at multiple lysine residues), or poly-ubiquitylation, in which the poly-ubiquitin chain is elongated on certain Lys residue on the ubiquitin by sequential cycles of ubiquitin assembling [84, 85].

Ubiquitin chain linkages. There are seven lysine residues in the ubiquitin, among which K48 and K63 are two major sites for poly-ubiquitin chain elongation (Fig. 1a). The fate of an Ub chain-tagged protein may be determined by the type of the Ub linkage. K48-linked poly-ubiquitin chain-attached proteins are usually detained and destructed by 26S proteasome, whereas K63-linked poly-ubiquitylation or mono-ubiquitylation and multi-ubiquitylation generally function in other biological processes.

Appendix 2 RING and HECT E3s

RING type E3s. The RING E3 ligases facilitate E2-dependent ubiquitylation that interact and bring target proteins close enough to let E2s transfer ubiquitin directly to specific internal Lys residues of the substrates. Those E3s can work by monomers, dimmers or complexes containing multiple subunits. RING E3 complexes include cullin RING ligase (CRL) superfamily (includes SCF, BTB, and SOCS/BC type of E3 complexes) and anaphase-promoting complex (APC) [86, 87].

HECT type E3s. HECT E3s receipt Ub molecule, by form an Ub-thioester intermediate, from their E2 donors and then transfer those ubiquitins onto their specific interacting preys. The characteristic HECT domain is a bilobal domain with an N lobe and a C lobe. Based on the N terminus architecture, HECT E3s can be generally divided into Nedd4 family (contains successive C2 and WW domains from N terminus) (Fig. 1b), HERC family (contains the RLD domain in N terminus), and other HECTs.

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Cao, Y., Zhang, L. A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks. Cell. Mol. Life Sci. 70, 2305–2317 (2013). https://doi.org/10.1007/s00018-012-1170-7

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