Myxoma virus leukemia-associated protein is responsible for major histocompatibility complex class I and Fas-CD95 down-regulation and defines scrapins, a new group of surface cellular receptor abductor proteins.
Down-modulation of major histocompatibility class I (MHC-I) molecules is a viral strategy for survival in the host. Myxoma virus, a member of the Poxviridae family responsible for rabbit myxomatosis, can down-modulate the expression of MHC-I molecules, but the viral factor(s) has not been described. We cloned and characterized a gene coding for an endoplasmic reticulum (ER)-resident protein containing an atypical zinc finger and two transmembrane domains, which we called myxoma virus leukemia-associated protein (MV-LAP). MV-LAP down-regulated surface MHC-I and Fas-CD95 molecules upon transfection; the mechanism probably involves an exacerbation of endocytosis and was lost when the ER retention signal was removed. In addition, the lytic activity of MHC-I-restricted antigen-specific cytolytic T lymphocytes (CTL) against myxoma virus-infected antigen-presenting target cells was significantly reduced, revealing a strong correlation between MHC-I down-regulation by MV-LAP and CTL killing in vitro. In vivo experiments with a knockout virus showed that MV-LAP is a virulence factor, potentially involved in the immunosuppression characteristic of myxomatosis. Data bank analysis revealed that MV-LAP has homologs in herpesviruses and other poxviruses. We propose the name "scrapins" to define a new group of ER-resident surface cellular receptor abductor proteins. The down-regulation of cell surface molecules by scrapins probably helps protect infected cells during viral infections.
Guerin
Jean-Luc
JL
UMR 960 Microbiologie Moléculaire, Institut National de la Recherche Agronomique and Ecole Nationale Vétérinaire, 31076 Toulouse, France.
Gelfi
Jacqueline
J
Boullier
Severine
S
Delverdier
Maxence
M
Bellanger
Frederique-Anne
FA
Bertagnoli
Stephane
S
Drexler
Ingo
I
Sutter
Gerd
G
Messud-Petit
Frederique
F
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009233:Myxoma virus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D009234:Myxomatosis, Infectious / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D019014:fas Receptor / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; C450447:MV-LAP protein, Myoxoma; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D014764:Viral Proteins; D019014:fas Receptor