Article
- The EMBO Journal (2006) 25, 1635 - 1645
- doi:10.1038/sj.emboj.7601056
Published online: 6 April 2006
Subject Categories:
Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules
Lidia M Duncan1, Siân Piper2, Roger B Dodd1, Mark K Saville3, Chris M Sanderson4, J Paul Luzio2 and Paul J Lehner1
- Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, UK
- Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- Cancer Research UK, Cell Transformation Research Group, Department of Surgery and Molecular Oncology, University of Dundee, Scotland, UK
- Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, UK
Correspondence to:
Paul J Lehner, Department of Medicine, Cambridge Institute for Medical Research, Lab 5.19, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK. Tel.: +44 1223 762113; Fax: +44 1223 762640; E-mail: pjl30@cam.ac.uk
Received 22 December 2005; Accepted 27 February 2006
Abstract
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.
Keywords:
- antigen presentation,
- MHC class I molecules,
- ubiquitin,
- viral evasion
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