title: The murine gamma-herpesvirus-68 MK3 protein causes TAP degradation independent of MHC class I heavy chain degradation.
abstract: The murine gamma-herpesvirus-68 MK3 protein has an intricate interaction with the peptide loading complex that involves MK3 stabilization, a rapid degradation of MHC class I heavy chains, and a slower degradation of TAP. Here we have used tapasin chimeras to distinguish functionally the different immune evasion mechanisms of MK3. Tapasin was cloned in two alternatively spliced forms that differed by a single transmembrane valine residue. Each restored antigen presentation and MK3 function in tapasin-deficient cells. The transmembrane/cytoplasmic portion of tapasin, linked to the extracellular domain of CD8, also restored TAP stability and MK3 stability in tapasin-deficient cells. MK3 did not associate with or degrade MHC class I in these cells, which lacked the endoplasmic reticulum domain of tapasin, but degraded TAP at least as efficiently as when full-length tapasin was present. The un-degraded MHC class I consequently showed impaired maturation. The fact that MK3 required intact tapasin to degrade MHC class I but only the transmembrane/cytoplasmic portion of tapasin to degrade TAP indicated that these two immune evasion functions operate independently.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Boname
authors.forename: Janet S
authors.initials: JS
authors.lastname: May
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000950:Antigens, Ly / Q000378:metabolism*; D017920:Antiporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018142:Gammaherpesvirinae / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; D017920:Antiporters; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C032907:Q surface antigens; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C107762:tapasin; D004247:DNA