Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation

EMBO J. 2002 May 15;21(10):2418-29. doi: 10.1093/emboj/21.10.2418.


The Kaposi's sarcoma-associated herpes virus gene product K3 (KK3) subverts the MHC class I antigen presentation pathway by downregulating MHC class I from the plasma membrane. We now show that KK3 associates with MHC class I molecules and promotes ubiquitylation of class I after export from the endoplasmic reticulum. Ubiquitylation requires the KK3 N-terminal plant homeodomain and provides the signal for class I internalization at the plasma membrane. Once internalized, ubiquitylated MHC class I is targeted to the late endocytic pathway, where it is degraded. Depletion by small interfering RNA of TSG101, a ubiquitin enzyme 2 variant protein involved in late endosomal sorting, prevents class I degradation and preserves cell surface class I expression in KK3-expressing cells. These results suggest a mechanism by which the KK3-induced class I ubiquitylation provides a signal for both internalization and sorting to the late endosomal pathway for degradation. KK3 is the first viral gene product that subverts the trafficking of a host protein via the ubiquitin-dependent endosomal sorting machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • Endosomal Sorting Complexes Required for Transport
  • HeLa Cells
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Leucine Zippers
  • Open Reading Frames
  • Protein Transport
  • Recombinant Proteins / metabolism
  • Transcription Factors / metabolism*
  • Transfection
  • Ubiquitin / metabolism*
  • Viral Proteins / metabolism*
  • Zinc Fingers


  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Histocompatibility Antigens Class I
  • K3 protein, Kaposi's sarcoma-associated herpesvirus
  • Recombinant Proteins
  • Transcription Factors
  • Tsg101 protein
  • Ubiquitin
  • Viral Proteins