van den Boomen, Dick J H2; Timms, Richard T2; Grice, Guinevere L2; Stagg, Helen R2; Dougan, Gordon3; Nathan, James A2; Lehner, Paul J2; Skjødt, Karsten4
1 Department of Cancer and Inflammation Research, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 University of Cambridge3 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom.4 Department of Cancer and Inflammation Research, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU
The US11 gene product of human cytomegalovirus promotes viral immune evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US11 initiates dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation. Despite the critical role for ubiquitin in this degradation pathway, the responsible E3 ligase is unknown. In a forward genetic screen for host ERAD components hijacked by US11 in near-haploid KBM7 cells, we identified TMEM129, an uncharacterized polytopic membrane protein. TMEM129 is essential and rate-limiting for US11-mediated MHC-I degradation and acts as a novel ER resident E3 ubiquitin ligase. TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. Together with its E2 conjugase Ube2J2, TMEM129 is responsible for the ubiquitination, dislocation, and subsequent degradation of US11-associated MHC-I. US11 engages two degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for "free" US11 degradation. Our data show that TMEM129 is a novel ERAD E3 ligase and the central component of a novel mammalian ERAD complex.
National Academy of Sciences. Proceedings, 2014, Vol 111, Issue 31