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

Abstract

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.

• Authors: Helen R Stagg, Mair Thomas, Dick van den Boomen, Emmanuel J H J Wiertz, Harry A Drabkin, Robert M Gemmill, Paul J Lehner
• Journal: The Journal of cell biology (J Cell Biol) Vol. 186 Issue 5 Pg. 685-92 (Sep 07 2009) ISSN: 1540-8140 [Electronic] United States
• PMID: 19720873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• RNF139 protein, human
• Receptors, Cell Surface
• Recombinant Fusion Proteins
• US2 protein, Varicellovirus
• Ubiquitin
• Viral Envelope Proteins

Topics

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