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van de Weijer, M.L.* ; Bassik, M.C.* ; Luteijn, R.D.* ; Voorburg, C.M.* ; Lohuis, M.A.* ; Kremmer, E. ; Hoeben, R.C.* ; Leproust, E.M.* ; Chen, S.* ; Hoelen, H.* ; Ressing, M.E.* ; Patena, W.* ; Weissman, J.S.* ; McManus, M.T.* ; Wiertz, E.J.* ; Lebbink, R.J.*

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

Nat. Commun. 5:3832 (2014)
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Misfolded ER proteins are retrotranslocated into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 exploits this ER-associated protein degradation (ERAD) pathway to downregulate HLA class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. US11-mediated degradation of HLA class I has been instrumental in the identification of key components of mammalian ERAD, including Derlin-1, p97, VIMP and SEL1L. Despite this, the process governing retrotranslocation of the substrate is still poorly understood. Here using a high-coverage genome-wide shRNA library, we identify the uncharacterized protein TMEM129 and the ubiquitin-conjugating E2 enzyme UBE2J2 to be essential for US11-mediated HLA class I downregulation. TMEM129 is an unconventional C4C4-type RING finger E3 ubiquitin ligase that resides within a complex containing various other ERAD components, including Derlin-1, Derlin-2, VIMP and p97, indicating that TMEM129 is an integral part of the ER-resident dislocation complex mediating US11-induced HLA class I degradation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Class-i Molecules; Reticulum-associated Degradation; Large Gene Lists; Endoplasmic-reticulum; Membrane-protein; Ubiquitin Ligase; Quality-control; Heavy-chains; Antigen Presentation; Retro-translocation
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 5, Issue: , Pages: , Article Number: 3832 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501793-001
PubMed ID 24807418
DOI 10.1038/ncomms4832
WOS ID WOS:000337373200007
Scopus ID 84900018251
Erfassungsdatum 2014-05-10
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