Mitochondrial cell death suppressors carried by human and murine cytomegalovirus confer resistance to proteasome inhibitor-induced apoptosis.
Human cytomegalovirus carries a mitochondria-localized inhibitor of apoptosis (vMIA) that is conserved in primate cytomegaloviruses. We find that inactivating mutations within UL37x1, which encodes vMIA, do not substantially affect replication in TownevarATCC (Towne-BAC), a virus that carries a functional copy of the betaherpesvirus-conserved viral inhibitor of caspase 8 activation, the UL36 gene product. In Towne-BAC infection, vMIA reduces susceptibility of infected cells to intrinsic death induced by proteasome inhibition. vMIA is sufficient to confer resistance to proteasome inhibition when expressed independent of viral infection. Murine cytomegalovirus m38.5, whose position in the viral genome is analogous to UL37x1, exhibits mitochondrial association and functions in much the same manner as vMIA in inhibiting intrinsic cell death. This work suggests a common role for vMIA in rodent and primate cytomegaloviruses, modulating the threshold of virus-infected cells to intrinsic cell death.
McCormick
A Louise
AL
Department of Microbiology & Immunology, Fairchild Science Building, Stanford University School of Medicine, Stanford, CA 95304-5124, USA.
Meiering
Christopher D
CD
Smith
Geoffrey B
GB
Mocarski
Edward S
ES
D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007425:Intracellular Membranes / Q000737:chemistry; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018146:Muromegalovirus / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D017874:Immediate-Early Proteins; D024101:Mitochondrial Proteins; D061988:Proteasome Inhibitors; C078035:UL36 protein, Human herpesvirus 1; C420323:UL37 protein, Human herpesvirus 5; D014764:Viral Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex