Viral degradation of the MHC class I peptide loading complex.
The murine gamma-herpesvirus-68 MK3 protein inhibits CD8(+) T cell recognition by ubiquitinating the cytoplasmic tails of classical MHC class I heavy chains. Here we show that MK3 also provides the first example of a protein that degrades tapasin and TAP. The degradation was MK3 RING finger dependent and primarily affected TAP. MK3 associated with TAP1 in the absence of tapasin or TAP2, suggesting that TAP1 was a primary binding partner in the peptide loading complex. TAP2 also played a major role in MK3 stability and function. By degrading TAP, therefore, MK3 limited its own expression. However, TAP degradation also broadened the MK3 inhibitory repertoire and achieved a remarkable resistance to MHC class I upregulation by interferon-gamma, suggesting that it represents a specific adaptation to immune evasion in lymphoid tissue.
Boname
Jessica M
JM
Division of Virology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
de Lima
Brigitte D
BD
Lehner
Paul J
PJ
Stevenson
Philip G
PG
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D046911:Macromolecular Substances; D051379:Mice; D010455:Peptides / Q000378:metabolism*; D018144:Rhadinovirus / Q000472:pathogenicity; D014452:Ubiquitins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D046911:Macromolecular Substances; D010455:Peptides; C032907:Q surface antigens; C489516:Tap2 protein, mouse; D014452:Ubiquitins; D014764:Viral Proteins; D007371:Interferon-gamma