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

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Listed:
  • Michael L. van de Weijer

    (Medical Microbiology, University Medical Center Utrecht)

  • Michael C. Bassik

    (California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California
    Present address: Department of Genetics, Stanford University, California 94305, USA)

  • Rutger D. Luteijn

    (Medical Microbiology, University Medical Center Utrecht)

  • Cornelia M. Voorburg

    (Medical Microbiology, University Medical Center Utrecht)

  • Mirjam A.M. Lohuis

    (Medical Microbiology, University Medical Center Utrecht)

  • Elisabeth Kremmer

    (Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Molecular Immunology)

  • Rob C. Hoeben

    (Leiden University Medical Center)

  • Emily M. LeProust

    (Genomics Solution Unit, Agilent Technologies Inc.
    Present address: Twist Bioscience, San Francisco, California 94158, USA)

  • Siyuan Chen

    (Genomics Solution Unit, Agilent Technologies Inc.
    Present address: Twist Bioscience, San Francisco, California 94158, USA)

  • Hanneke Hoelen

    (Medical Microbiology, University Medical Center Utrecht)

  • Maaike E. Ressing

    (Medical Microbiology, University Medical Center Utrecht
    Leiden University Medical Center)

  • Weronika Patena

    (California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California
    University of California
    Present address: Carnegie Institution for Science, Department of Plant Biology, Stanford, California 94305, USA)

  • Jonathan S. Weissman

    (California Institute for Quantitative Biomedical Research, Howard Hughes Medical Institute, University of California)

  • Michael T. McManus

    (University of California)

  • Emmanuel J.H.J. Wiertz

    (Medical Microbiology, University Medical Center Utrecht)

  • Robert Jan Lebbink

    (Medical Microbiology, University Medical Center Utrecht)

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.

Suggested Citation

  • Michael L. van de Weijer & Michael C. Bassik & Rutger D. Luteijn & Cornelia M. Voorburg & Mirjam A.M. Lohuis & Elisabeth Kremmer & Rob C. Hoeben & Emily M. LeProust & Siyuan Chen & Hanneke Hoelen & Ma, 2014. "A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation," Nature Communications, Nature, vol. 5(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4832
    DOI: 10.1038/ncomms4832
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