The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Helen R Stagg, Mair Thomas, Dick van den Boomen, Emmanuel J H J Wiertz, Harry A Drabkin, Robert M Gemmill, Paul J Lehner

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination. Depletion of TRC8 prevents MHC I ubiquitination and dislocation by US2 and restores cell surface MHC I. TRC8 forms an integral part of a novel multiprotein ER complex that contains MHC I, US2, and signal peptide peptidase. Our data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD.

Original languageEnglish
Pages (from-to)685-92
Number of pages8
JournalJournal of Cell Biology
Volume186
Issue number5
DOIs
Publication statusPublished - 31 Aug 2009

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Endoplasmic Reticulum/metabolism
  • HeLa Cells
  • Histocompatibility Antigens Class I/genetics
  • Humans
  • Major Histocompatibility Complex
  • Mutation
  • RNA Interference
  • Receptors, Cell Surface/genetics
  • Recombinant Fusion Proteins/genetics
  • Ubiquitin/metabolism
  • Viral Envelope Proteins/genetics

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