title: 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.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Dick J H
authors.initials: DJ
authors.lastname: van den Boomen
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Richard T
authors.initials: RT
authors.lastname: Timms
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Guinevere L
authors.initials: GL
authors.lastname: Grice
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Helen R
authors.initials: HR
authors.lastname: Stagg
authors.affiliation: Department of Cancer and Inflammation, University of Southern Denmark, 5000 Odense, Denmark; and.
authors.forename: Karsten
authors.initials: K
authors.lastname: Skødt
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: James A
authors.initials: JA
authors.lastname: Nathan
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom; pjl30@cam.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology; D060746:Endoplasmic Reticulum-Associated Degradation; D005814:Genes, Viral; D005820:Genetic Testing; D006238:Haploidy; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C487709:DERL1 protein, human; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C117384:SEL1L protein, human; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; C489966:UBE2J2 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C482345:SYVN1 protein, human; C000591994:TMEM129 protein, human; D044767:Ubiquitin-Protein Ligases