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

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, Maaike E Ressing, Weronika Patena, Jonathan S Weissman, Michael T McManus, Emmanuel J H J Wiertz, Robert Jan Lebbink

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article number3832
JournalNature Communications
Publication statusPublished - 8 May 2014
Externally publishedYes


  • Adenosine Triphosphatases/genetics
  • Cell Line, Tumor
  • Clustered Regularly Interspaced Short Palindromic Repeats/genetics
  • Cytomegalovirus/genetics
  • Cytomegalovirus Infections
  • Down-Regulation
  • Endoplasmic Reticulum/pathology
  • Endoplasmic Reticulum-Associated Degradation
  • HEK293 Cells
  • Histocompatibility Antigens Class I/biosynthesis
  • Humans
  • Membrane Proteins/genetics
  • Nuclear Proteins/genetics
  • Protein Folding
  • Proteins/genetics
  • RNA Interference
  • RNA, Small Interfering
  • RNA-Binding Proteins/genetics
  • Selenoproteins/genetics
  • U937 Cells
  • Ubiquitin-Conjugating Enzymes/genetics
  • Ubiquitin-Protein Ligases/genetics
  • Viral Proteins/genetics


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