TMEM129 polyubiquitinates HLA (MHC class I heavy chain) bound to cytomegalovirus US11

Stable Identifier
Reaction [omitted]
Homo sapiens
Related Species
Human cytomegalovirus
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The E3 ubiquitin ligase TMEM129 transfers ubiquitin from the E2 ubiquitin conjugases UBE2J2 and UBE2K to a MHC class I heavy chain bound by the human cytomegalovirus US11 protein (van de Weijer et al. 2014, van den Boomen et al. 2014, Flierman et al. 2006, reviewed in van den Boomen and Lehner 2015). TMEM129 is located in the endoplasmic reticulum membrane in a complex containing DERL1, UBE2J2 and UBE2K, VIMP and VCP. After polyubiquitination, MHC class I heavy chain is retrotranslocated by the AAA ATPase VCP to the cytosol (Ye et al. 2001) where it is deglycosylated by NGLYI and degraded by the proteasome (Wiertz et al. 1996). US11 is released after the reaction and, if unable to bind another MHC I heavy chain, US11 is ubiquitinated by the HRD1-SEL1L E3 ubiquitin ligase complex and itself degraded by the proteasome (van den Boomen et al. 2014). This self-regulatory loop allows the amount of US11 in the cell to be buffered against the amount of MHC I molecules.
Literature References
PubMed ID Title Journal Year
25030448 TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I

Nathan, JA, Dougan, G, Stagg, HR, Skødt, K, Timms, RT, van den Boomen, DJ, Grice, GL, Lehner, PJ

Proc. Natl. Acad. Sci. U.S.A. 2014
15215855 A membrane protein required for dislocation of misfolded proteins from the ER

Lilley, BN, Ploegh, HL

Nature 2004
8625414 The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol

Sun, L, Ploegh, HL, Bogyo, M, Wiertz, EJ, Geuze, HJ, Jones, TR

Cell 1996
24807418 A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation

van de Weijer, ML, Hoelen, H, Lebbink, RJ, Voorburg, CM, Chen, S, Ressing, ME, Wiertz, EJ, Kremmer, E, Lohuis, MA, Hoeben, RC, Luteijn, RD, Bassik, MC, McManus, MT, Leproust, EM, Weissman, JS, Patena, W

Nat Commun 2014
11740563 The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol

Meyer, HH, Ye, Y, Rapoport, TA

Nature 2001
15215856 A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol

Shibata, Y, Ron, D, Yun, C, Rapoport, TA, Ye, Y

Nature 2004
26210183 Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I

van den Boomen, DJ, Lehner, PJ

Mol. Immunol. 2015
Catalyst Activity

ubiquitin protein ligase activity of US11:HLA:TMEM129:DERL1:VIMP:VCP:Ub:UBE2J2 [endoplasmic reticulum membrane]

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