The interferon stimulator mitochondrial antiviral signaling protein facilitates cell death by disrupting the mitochondrial membrane potential and by activating caspases.
Interferon (IFN) signaling is initiated by the recognition of viral components by host pattern recognition receptors. Dengue virus (DEN) triggers IFN-beta induction through a molecular mechanism involving the cellular RIG-I/MAVS signaling pathway. Here we report that the MAVS protein level is reduced in DEN-infected cells and that caspase-1 and caspase-3 cleave MAVS at residue D429. In addition to its well-known function in IFN induction, MAVS is also a proapoptotic molecule that triggers disruption of the mitochondrial membrane potential and activation of caspases. Although different domains are required for the induction of cytotoxicity and IFN, caspase cleavage at residue 429 abolished both functions of MAVS. The apoptotic role of MAVS in viral infection and double-stranded RNA (dsRNA) stimulation was demonstrated in cells with reduced endogenous MAVS expression induced by RNA interference. Even though IFN-beta promoter activation was largely suppressed, DEN production was not affected greatly in MAVS knockdown cells. Instead, DEN- and dsRNA-induced cell death and caspase activation were delayed and attenuated in the cells with reduced levels of MAVS. These results reveal a new role of MAVS in the regulation of cell death beyond its well-known function of IFN induction in antiviral innate immunity.
Yu
Chia-Yi
CY
Institute of Biomedical Sciences, Academia Sinica, Taiwan, Republic of China.
Chiang
Ruei-Lin
RL
Chang
Tsung-Hsien
TH
Liao
Ching-Len
CL
Lin
Yi-Ling
YL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D003715:Dengue / Q000276:immunology; D004789:Enzyme Activation; D018067:Flaviviridae / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007369:Interferon Inducers / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D007527:Isoenzymes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D011070:Poly I-C / Q000276:immunology; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D007369:Interferon Inducers; D007527:Isoenzymes; C505371:MAVS protein, human; D012330:RNA, Double-Stranded; D011993:Recombinant Fusion Proteins; D007372:Interferons; D020169:Caspases; D011070:Poly I-C