A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation PMID: 24807418

ADC Targets in Oncology

2026-04-10

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

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

Michael L van de Weijer ¹ , Michael C Bassik ² , Rutger D Luteijn ¹ , Cornelia M Voorburg ¹ , Mirjam A M Lohuis ¹ , Elisabeth Kremmer ³ , Rob C Hoeben ⁴ , Emily M LeProust ⁵ , Siyuan Chen ⁵ , Hanneke Hoelen ¹ , Maaike E Ressing ⁶ , Weronika Patena ⁷ , Jonathan S Weissman ⁸ , Michael T McManus ⁹ , Emmanuel J H J Wiertz ¹⁰ , Robert Jan Lebbink ¹⁰

Affiliations

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.