Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.
Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the mitochondrial antiviral signaling protein, MAVS, that activates NF-kappaB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host-pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
Li
Xiao-Dong
XD
Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Sun
Lijun
L
Seth
Rashu B
RB
Pineda
Gabriel
G
Chen
Zhijian J
ZJ
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000201:enzymology* / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D016899:Interferon-beta / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002352:Carrier Proteins; D003545:Cysteine; D016899:Interferon-beta; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus