Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase

Science. 2005 Jul 1;309(5731):127-30. doi: 10.1126/science.1110340.

Abstract

Ubiquitination controls a broad range of cellular functions. The last step of the ubiquitination pathway is regulated by enzyme type 3 (E3) ubiquitin ligases. E3 enzymes are responsible for substrate specificity and catalyze the formation of an isopeptide bond between a lysine residue of the substrate (or the N terminus of the substrate) and ubiquitin. MIR1 and MIR2 are two E3 ubiquitin ligases encoded by Kaposi's sarcoma-associated herpesvirus that mediate the ubiquitination of major histocompatibility complex class I (MHC I) molecules and subsequent internalization. Here, we found that MIR1, but not MIR2, promoted down-regulation of MHC I molecules lacking lysine residues in their intracytoplasmic domain. In the presence of MIR1, these MHC I molecules were ubiquitinated, and their association with ubiquitin was sensitive to beta2-mercaptoethanol, unlike lysine-ubiquitin bonds. This form of ubiquitination required a cysteine residue in the intracytoplasmic tail of MHC I molecules. An MHC I molecule containing a single cysteine residue in an artificial glycine and alanine intracytoplasmic domain was endocytosed and degraded in the presence of MIR1. Thus, ubiquitination can occur on proteins lacking accessible lysines or an accessible N terminus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Down-Regulation
  • Endocytosis
  • HLA-B7 Antigen / chemistry
  • HLA-B7 Antigen / genetics
  • HLA-B7 Antigen / metabolism*
  • Herpesvirus 8, Human / enzymology*
  • Humans
  • Lysine / metabolism
  • Mutation
  • Protein Structure, Tertiary
  • Serine / chemistry
  • Serine / metabolism
  • Transduction, Genetic
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • HLA-B7 Antigen
  • Ubiquitin
  • Serine
  • MIR1 E3 ubiquitin ligase, KSHV
  • Ubiquitin-Protein Ligases
  • Lysine
  • Cysteine