TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I.

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.
Mesh Terms:
Amino Acid Sequence, Biocatalysis, Cytosol, Down-Regulation, Endoplasmic Reticulum, Endoplasmic Reticulum-Associated Degradation, Genes, Viral, Genetic Testing, Haploidy, Herpesvirus 1, Human, Histocompatibility Antigens Class I, Humans, Membrane Proteins, Molecular Sequence Data, Protein Binding, Protein Stability, Proteins, Proteolysis, RNA-Binding Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination, Viral Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Aug. 05, 2014
Download Curated Data For This Publication
185532
Switch View:
  • Interactions 5