Cell death suppression by cytomegaloviruses.
Cytomegaloviruses (CMVs), a subset of betaherpesviruses, employ multiple strategies to suppress apoptosis in infected cells and thus to delay their death. Human cytomegalovirus (HCMV) encodes at least two proteins that directly interfere with the apoptotic signaling pathways, viral inhibitor of caspase-8-induced apoptosis vICA (pUL36), and mitochondria-localized inhibitor of apoptosis vMIA (pUL37 x 1). vICA associates with pro-caspase-8 and appears to block its recruitment to the death-inducing signaling complex (DISC), a step preceding caspase-8 activation. vMIA binds and sequesters Bax at mitochondria, and interferes with BH3-only-death-factor/Bax-complex-mediated permeabilization of mitochondria. vMIA does not seem to either interact with Bak, a close structural and functional homologue of Bax, or to suppress Bak-mediated permeabilization of mitochondria and Bak-mediated apoptosis. All sequenced betaherpesviruses, including CMVs, encode close homologues of vICA, and those vICA homologues that have been tested, were found to be functional cell death suppressors. Overt sequence homologues of vMIA were found only in the genomes of primate CMVs, but recent observations made with murine CMV (MCMV) indicate that non-primate CMVs may also encode a cell death suppressor functionally resembling vMIA. The exact physiological roles and relative contributions of vMIA and vICA in suppressing death of CMV-infected cells in vivo have not been elucidated. There is strong evidence that the cell death suppressing function of vMIA is indispensable, and that vICA is dispensable for replication of HCMV. In addition to suppressed caspase-8 activation and sequestered Bax, CMV-infected cells display several other phenomena, less well characterized, that may diminish, directly or indirectly the extent of cell death.
Goldmacher
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ImmunoGen, Inc., 128 Sidney St., Cambridge, MA 02139, USA. victor.goldmacher@immunogen.com
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D003587:Cytomegalovirus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins / Q000737:chemistry / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases