期刊
EMBO JOURNAL
卷 25, 期 8, 页码 1635-1645出版社
WILEY
DOI: 10.1038/sj.emboj.7601056
关键词
antigen presentation; MHC class I molecules; ubiquitin; viral evasion
资金
- MRC [G9800943, G9310915] Funding Source: UKRI
- Medical Research Council [G9310915, G9800943] Funding Source: researchfish
- Medical Research Council [G9310915, G9800943, G0600823] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
MHC class I molecules display peptides from endogenous and viral proteins for immunosurveillance by cytotoxic T lymphocytes (CTL). The importance of the class I pathway is emphasised by the remarkable strategies employed by different viruses to downregulate surface class I and avoid CTL recognition. The K3 gene product from Kaposi's sarcoma-associated herpesvirus (KSHV) is a viral ubiquitin E3 ligase which ubiquitinates and degrades cell surface MHC class I molecules. We now show that modification of K3-associated class I by lysine-63-linked polyubiquitin chains is necessary for their efficient endocytosis and endolysosomal degradation and present three lines of evidence that monoubiquitination of class I molecules provides an inefficient internalisation signal. This lysine-63-linked polyubiquitination requires both UbcH5b/c and Ubc13-conjugating enzymes for initiating mono- and subsequent polyubiquitination of class I, and the clathrin-dependent internalisation is mediated by the epsin endocytic adaptor. Our results explain how lysine-63-linked polyubiquitination leads to degradation by an endolysosomal pathway and demonstrate a novel mechanism for endocytosis and endolysosomal degradation of class I, which may be applicable to other receptors.
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