Efficient internalization of MHC I requires lysine-11 and lysine-63 mixed linkage polyubiquitin chains

Jessica M Boname, Mair Thomas, Helen R Stagg, Ping Xu, Junmin Peng, Paul J Lehner

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)210-20
Number of pages11
JournalTraffic
Volume11
Issue number2
DOIs
Publication statusPublished - 4 Jan 2010

Keywords

  • Amino Acid Sequence
  • Endocytosis/physiology
  • Genetic Linkage
  • HeLa Cells
  • Humans
  • Lysine/metabolism
  • Major Histocompatibility Complex/physiology
  • Mass Spectrometry
  • Molecular Sequence Data
  • Mutation
  • Polyubiquitin/chemistry
  • Receptors, Cell Surface
  • Signal Transduction
  • Ubiquitin-Protein Ligases/metabolism
  • Ubiquitination

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