HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation.

Abstract

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 I-β2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.

• Authors: Marian L Burr, Florencia Cano, Stanislava Svobodova, Louise H Boyle, Jessica M Boname, Paul J Lehner
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 5 Pg. 2034-9 (Feb 01 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21245296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• RNA, Small Interfering
• UBE2J1 protein, human
• Ubiquitin-Conjugating Enzymes
• SYVN1 protein, human
• Ubiquitin-Protein Ligases

Topics

• Endoplasmic Reticulum (metabolism)
• HeLa Cells
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Hydrolysis
• Protein Folding
• RNA, Small Interfering (genetics)
• Ubiquitin-Conjugating Enzymes (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination