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

Abstract

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.

• Authors: Dick J H van den Boomen, Richard T Timms, Guinevere L Grice, Helen R Stagg, Karsten Skødt, Gordon Dougan, James A Nathan, Paul J Lehner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 31 Pg. 11425-30 (Aug 05 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25030448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DERL1 protein, human
• Histocompatibility Antigens Class I
• Membrane Proteins
• Proteins
• RNA-Binding Proteins
• SEL1L protein, human
• US11 protein, herpesvirus
• Viral Proteins
• UBE2J2 protein, human
• Ubiquitin-Conjugating Enzymes
• SYVN1 protein, human
• TMEM129 protein, human
• Ubiquitin-Protein Ligases

Topics

• Amino Acid Sequence
• Biocatalysis
• Cytosol (metabolism)
• Down-Regulation
• Endoplasmic Reticulum (enzymology)
• Endoplasmic Reticulum-Associated Degradation
• Genes, Viral
• Genetic Testing
• Haploidy
• Herpesvirus 1, Human (genetics, physiology)
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Membrane Proteins (metabolism)
• Molecular Sequence Data
• Protein Binding
• Protein Stability
• Proteins (metabolism)
• Proteolysis
• RNA-Binding Proteins (genetics, metabolism)
• Ubiquitin-Conjugating Enzymes (metabolism)
• Ubiquitin-Protein Ligases (chemistry, metabolism)
• Ubiquitination
• Viral Proteins (genetics, metabolism)