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HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation
Marian L. Burr, Florencia Cano, Stanislava Svobodova, Louise H. Boyle, Jessica M. Boname, Paul J. Lehner and Peter Cresswell
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 5 (February 1, 2011), pp. 2034-2039
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41001812
Page Count: 6
You can always find the topics here!Topics: HeLa cells, Small interfering RNA, Enzymes, Ubiquitins, Yeasts, Cytosol, Endoplasmic reticulum, Z score, Signals, COS cells
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The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. MHC class I heavy chains that fail to achieve their native conformation in complex with β2-microglobulin (β2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination of the MHC class I heavy chain and its dislocation from the ER to the cytosol for proteasome-mediated degradation, although the cellular machinery involved in this process is unknown. Using an siRNA functional screen in β2m-depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains. HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosis-associated HFE-C282Y mutant, which is unable to bind β2m. In the absence of HRD1, misfolded HLA-B27 accumulated in cells with a normal MHC class I assembly pathway, and HRD1 depletion prevented the appearance of low levels of cytosolic unfolded MHC I heavy chains. HRD1 and UBE2J1 associate in a complex together with non-β2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC Iβ2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.
Proceedings of the National Academy of Sciences of the United States of America © 2011 National Academy of Sciences