期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 12, 页码 6978-6985出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0904154
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资金
- Wellcome Trust
- Medical Research Council [G9800943, G0600823] Funding Source: researchfish
- MRC [G9800943, G0600823] Funding Source: UKRI
The Kaposi's sarcoma-associated herpesvirus-encoded ubiquitin E3 ligase K3 ubiquitinates cell-surface MHC class I molecules ( MHC I), causing the internalization and degradation of MHC I via the endolysosomal pathway. K3 recruits the cellular E2 ubiquitin-conjugating enzyme Ubc13 to generate lysine-63-linked polyubiquitin chains on MHC I, leading to the clathrin-mediated endocytosis and lysosomal degradation of MHC I. In this study, we identify a ubiquitin isoleucine-44-alanine mutant (I44A) that inhibits K3-mediated downregulation of MHC I by preventing MHC I polyubiqitination. This E3-specific inhibition by I44A prevents dissociation of the MHC I-K3-Ubc13-ubiquitin complex, allows the in vivo visualization of a transient substrate-E3-E2-ubiquitin complex interaction, and highlights a potential substrate hierarchy between the different MHC I alleles down-regulated by K3. The I44A mutant also increases cell-surface MHC I expression in control cells in the absence of K3, predicting the presence of an endogenous E3 ubiquitin ligase required for cell-surface MHC I regulation. The Journal of Immunology, 2010, 184: 6978-6985.
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