Journal
TRAFFIC
Volume 11, Issue 2, Pages 210-220Publisher
WILEY
DOI: 10.1111/j.1600-0854.2009.01011.x
Keywords
endocytosis; K5; lysine-11; lysine-63; MHC class I; mixed linkage polyubiquitin chains; polyubiquitination; ubiquitin
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Funding
- Wellcome Trust
- Cambridge University Hospitals BRC
- NIH [AG025688]
- MRC [G0600823, G9800943] Funding Source: UKRI
- Medical Research Council [G0600823, G9800943] Funding Source: researchfish
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The downregulation of cell surface receptors by endocytosis is a fundamental requirement for the termination of signalling responses and ubiquitination is a critical regulatory step in receptor regulation. The K5 gene product of Kaposi's sarcoma-associated herpesvirus is an E3 ligase that ubiquitinates and downregulates several cell surface immunoreceptors, including major histocompatibility complex (MHC) class I molecules. Here, we show that K5 targets the membrane proximal lysine of MHC I for conjugation with mixed linkage polyubiquitin chains. Quantitative mass spectrometry revealed an increase in lysine-11, as well as lysine-63, linked polyubiquitin chains on MHC I in K5-expressing cells. Using a combination of mutant ubiquitins and MHC I molecules expressing a single cytosolic lysine residue, we confirm a functional role for lysines-11 and -63 in K5-mediated MHC I endocytosis. We show that lysine-11 linkages are important for receptor endocytosis, and that complex mixed linkage polyubiquitin chains are generated in vivo.
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