The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol.
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.
Wiertz
E J
EJ
Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Jones
T R
TR
Sun
L
L
Bogyo
M
M
Geuze
H J
HJ
Ploegh
H L
HL
D001254:Astrocytoma; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology*; D003600:Cytosol / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D015967:Gene Expression Regulation, Viral; D005805:Genes, MHC Class I; D005814:Genes, Viral; D006031:Glycosylation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000138:chemical synthesis / Q000494:pharmacology; D016253:Microscopy, Immunoelectron; D009097:Multienzyme Complexes / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; C098734:carbobenzoxy-leucyl-leucyl-leucine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex