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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2011-2-2
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pubmed:abstractText |
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 ?2-microglobulin (?2m) 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 ?2m-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 ?2m. 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-?2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC I-?2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/21245296-10586062,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21245296-11978783,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21245296-9356458
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1091-6490
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
108
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2034-9
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pubmed:dateRevised |
2011-7-25
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pubmed:meshHeading |
pubmed-meshheading:21245296-Endoplasmic Reticulum,
pubmed-meshheading:21245296-HeLa Cells,
pubmed-meshheading:21245296-Histocompatibility Antigens Class I,
pubmed-meshheading:21245296-Humans,
pubmed-meshheading:21245296-Hydrolysis,
pubmed-meshheading:21245296-Protein Folding,
pubmed-meshheading:21245296-RNA, Small Interfering,
pubmed-meshheading:21245296-Ubiquitin-Conjugating Enzymes,
pubmed-meshheading:21245296-Ubiquitin-Protein Ligases,
pubmed-meshheading:21245296-Ubiquitination
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pubmed:year |
2011
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pubmed:articleTitle |
HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation.
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pubmed:affiliation |
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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