The murine cytomegalovirus immune evasion protein m4/gp34 forms biochemically distinct complexes with class I MHC at the cell surface and in a pre-Golgi compartment.
We have recently demonstrated that the murine CMV (MCMV) gene m4 is an immune evasion gene that protects MCMV-infected targets from some virus-specific CTL clones. m4 encodes m4/gp34, a 34-kDa glycoprotein that binds to major histocompatibility complex class I in the endoplasmic reticulum and forms a detergent-stable complex that is exported to the surface of the cell. To investigate how m4/gp34 promotes CTL evasion, we analyzed the assembly and export of m4/gp34-K(b) complexes. We found that 50-70% of K(b) exported over the course of MCMV infection was m4/gp34 associated. Because these complexes are present at the cell surface, it is possible that m4 mediates CTL evasion by interfering with contact between class I and receptors on the T cell. In addition, we found that K(b) retained by the MCMV immune evasion gene m152 formed a novel type of complex with Endo H-sensitive m4/gp34; these complexes are distinguished from the exported complexes by being stable in 1% digitonin and unstable in 1% Nonidet P-40. Because this association occurs in a pre-Golgi compartment, m4/gp34 might also interfere with Ag presentation by affecting some aspect of class I assembly, such as peptide loading. Although m4/gp34 requires beta(2)-microglobulin to bind class I, there was no significant binding of m4/gp34 to beta(2)-microglobulin in the absence of class I H chain, demonstrating that m4/gp34 forms Nonidet P-40-stable complexes specifically with folded conformations of class I. We conclude that m4/gp34 promotes immune evasion by a novel mechanism involving altered assembly and/or T cell recognition of class I molecules.
Kavanagh
D G
DG
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.
Koszinowski
U H
UH
Hill
A B
AB
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006023:Glycoproteins / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006183:H-2 Antigens / Q000378:metabolism*; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018146:Muromegalovirus / Q000276:immunology* / Q000472:pathogenicity; D017830:Octoxynol; D011092:Polyethylene Glycols / Q000737:chemistry; D021381:Protein Transport; D014764:Viral Proteins; D001613:beta 2-Microglobulin / Q000378:metabolism
D002352:Carrier Proteins; D006023:Glycoproteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D014764:Viral Proteins; D001613:beta 2-Microglobulin; C104832:gp34 protein, cytomegalovirus; C104783:m152 protein, cytomegalovirus; D011092:Polyethylene Glycols; D017830:Octoxynol; C010615:Nonidet P-40