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

The Journal of cell biology (2009-09-02)
Helen R Stagg, Mair Thomas, Dick van den Boomen, Emmanuel J H J Wiertz, Harry A Drabkin, Robert M Gemmill, Paul J Lehner
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.

MATERIALS
Product Number
Brand
Product Description

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Iodoacetamide, BioUltra
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N-Ethylmaleimide, crystalline, ≥98% (HPLC)
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Iodoacetamide, Single use vial of 56 mg
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N-Ethylmaleimide, BioUltra, ≥99.0% (HPLC)
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N-Ethylmaleimide, purum p.a., ≥99.0% (HPLC)
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