The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol

Cell. 1996 Mar 8;84(5):769-79. doi: 10.1016/s0092-8674(00)81054-5.

Abstract

Human cytomegalovirus (HCMV) down-regulates expression of MHC class I products by selective proteolysis. A single HCMV gene, US11, which encodes an endoplasmic reticulum (ER) resident type-I transmembrane glycoprotein, is sufficient to cause this effect. In US11+cells, MHC class I molecules are core-glycosylated and therefore inserted into the ER. They are degraded with a half-time of less than 1 min. A full length breakdown intermediate that has lost the single N-linked glycan in an N-glycanase-catalyzed reaction transiently accumulates in cells exposed to the protease inhibitors LLnL, Cbz-LLL, and lactacystin, identifying the proteasome as a key protease. Subcellular fractionation experiments show this intermediate to be cytosolic. Thus, US11 dislocates newly synthesized class I molecules from the ER to the cytosol, where they are acted upon by an N-glycanase and the proteasome.

Publication types

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

MeSH terms

  • Astrocytoma
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • Cytomegalovirus / genetics*
  • Cytomegalovirus / immunology*
  • Cytosol / immunology
  • Endoplasmic Reticulum / immunology*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Gene Expression Regulation, Viral*
  • Genes, MHC Class I*
  • Genes, Viral*
  • Glycosylation
  • Histocompatibility Antigens Class I / biosynthesis
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Leupeptins / chemical synthesis
  • Leupeptins / pharmacology
  • Microscopy, Immunoelectron
  • Multienzyme Complexes / metabolism*
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Leupeptins
  • Multienzyme Complexes
  • Protease Inhibitors
  • RNA-Binding Proteins
  • Recombinant Proteins
  • US11 protein, herpesvirus
  • Viral Proteins
  • carbobenzoxy-leucyl-leucyl-leucine
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex