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

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 pro...

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Bibliographic Details
Published in:The Journal of cell biology 2009-09, Vol.186 (5), p.685-692
Main Authors: Stagg, Helen R, Thomas, Mair, van den Boomen, Dick, Wiertz, Emmanuel J.H.J, Drabkin, Harry A, Gemmill, Robert M, Lehner, Paul J
Format: Article
Language:English
Subjects:
Animals
Antibodies
Cells
Cytosol
Endoplasmic Reticulum - metabolism
Fluorescence
Genes
Genetics
HeLa Cells
Histocompatibility Antigens Class I - genetics
Histocompatibility Antigens Class I - metabolism
Humans
Kidney cells
Major Histocompatibility Complex
Membrane proteins
Mutation
Oligonucleotides
P branes
Peptides
Proteases
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Ribonucleic acid
RNA
RNA Interference
Small interfering RNA
Ubiquitin - metabolism
Ubiquitins
Viral Envelope Proteins - genetics
Viral Envelope Proteins - metabolism
Viruses
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200906110