Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR alpha-chain.
Human cytomegalovirus (HCMV) has developed multiple strategies to escape immune recognition. Here, we demonstrate that HCMV down-regulates HLA-DR expression in infected interferon gamma (IFN-gamma)-stimulated fibroblasts at 1 day after infection. Decreased HLA-DR expression was not observed on cells infected with an HCMV strain lacking the pp65 gene (RVAD65), but was observed on cells transfected with the pp65 gene. HLA-DR expression accumulated in vacuoles near the nucleus in HCMV-infected, but not in uninfected or RVAD65-infected cells. In addition, the HLA-DR alpha-chain, but not the beta-chain or HLA-DM, was degraded in HCMV-infected but not in RVAD65-infected cells. Thus, the HCMV protein pp65 mediates decreased expression of HLA-DR, by mediating an accumulation of HLA class II molecules in lysosomes that results in degradation of the HLA-DR alpha-chain.
Odeberg
Jenny
J
Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Plachter
Bodo
B
Brandén
Lars
L
Söderberg-Nauclér
Cecilia
C
D001692:Biological Transport; D003587:Cytomegalovirus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005347:Fibroblasts / Q000648:ultrastructure / Q000821:virology; D005434:Flow Cytometry; D017353:Gene Deletion; D015870:Gene Expression; D006681:HLA-D Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008247:Lysosomes / Q000378:metabolism*; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D050832:Interferon-Stimulated Gene Factor 3; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; C079868:gamma interferon activation factor; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2