Efficient Internalization of MHC I Requires Lysine-11 and Lysine-63 Mixed Linkage Polyubiquitin Chains

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 ubiqu...

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Bibliographic Details
Published in:Traffic (Copenhagen, Denmark) Denmark), 2010-02, Vol.11 (2), p.210-220
Main Authors: Boname, Jessica M, Thomas, Mair, Stagg, Helen R, Xu, Ping, Peng, Junmin, Lehner, Paul J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
endocytosis
Endocytosis - physiology
Genetic Linkage
HeLa Cells
Humans
Lysine - metabolism
lysine-11
lysine-63
Major Histocompatibility Complex - physiology
Mass Spectrometry
MHC class I
mixed linkage polyubiquitin chains
Molecular Sequence Data
Mutation
Original
Polyubiquitin - chemistry
Polyubiquitin - metabolism
polyubiquitination
Receptors, Cell Surface
Signal Transduction
ubiquitin
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary: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.
ISSN:1398-9219
1600-0854
DOI:10.1111/j.1600-0854.2009.01011.x