Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death.
Human cytomegalovirus infection perturbs multiple cellular processes that could promote the release of proapoptotic stimuli. Consequently, it encodes mechanisms to prevent cell death during infection. Using rotenone, a potent inhibitor of the mitochondrial enzyme complex I (reduced nicotinamide adenine dinucleotide-ubiquinone oxido-reductase), we found that human cytomegalovirus infection protected cells from rotenone-induced apoptosis, a protection mediated by a 2.7-kilobase virally encoded RNA (beta2.7). During infection, beta2.7 RNA interacted with complex I and prevented the relocalization of the essential subunit genes associated with retinoid/interferon-induced mortality-19, in response to apoptotic stimuli. This interaction, which is important for stabilizing the mitochondrial membrane potential, resulted in continued adenosine triphosphate production, which is critical for the successful completion of the virus' life cycle. Complex I targeting by a viral RNA represents a refined strategy to modulate the metabolic viability of the infected host cell.
Reeves
Matthew B
MB
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK.
Davies
Andrew A
AA
McSharry
Brian P
BP
Wilkinson
Gavin W
GW
Sinclair
John H
JH
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000821:virology*; D018384:Oxidative Stress; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D022661:RNA, Untranslated; D012367:RNA, Viral; D012402:Rotenone; D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D042967:Electron Transport Complex I