Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor.
Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its 3C(pro) cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of 3C(pro) and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3C(pro) protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver.
Yang
Yan
Y
Center for Hepatitis Research, Institute for Human Infections and Immunity, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
Liang
Yuqiong
Y
Qu
Lin
L
Chen
Zeming
Z
Yi
Minkyung
M
Li
Kui
K
Lemon
Stanley M
SM
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004792:Enzyme Precursors / Q000378:metabolism*; D016679:Genome, Viral; D030041:Hepatitis A virus / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008253:Macaca mulatta; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism; D014775:Virus Activation; D014779:Virus Replication
C109754:3ABC protein, virus; D048868:Adaptor Proteins, Signal Transducing; D004792:Enzyme Precursors; D050835:Interferon Regulatory Factors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D003546:Cysteine Endopeptidases; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1