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Nat Commun. 2014 May 8;5:3832. doi: 10.1038/ncomms4832.

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

Author information

1
Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
2
1] Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2].
3
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Molecular Immunology, 81377 Munich, Germany.
4
Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZC Leiden, The Netherlands.
5
1] Genomics Solution Unit, Agilent Technologies Inc., Santa Clara, California 95051, USA [2].
6
1] Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands [2] Department of Molecular Cell Biology, Leiden University Medical Center, 2333ZC Leiden, The Netherlands.
7
1] Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA [2] Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA [3].
8
Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA.
9
Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
10
1] Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands [2].

Abstract

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.

PMID:
24807418
PMCID:
PMC4024746
DOI:
10.1038/ncomms4832
[Indexed for MEDLINE]
Free PMC Article

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