Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor
| Autor: | Stanley M. Lemon, Yuqiong Liang, Yan Yang, Lin Qu, Zeming Chen, Min Kyung Yi, Kui Li |
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| Rok vydání: | 2007 |
| Předmět: |
Interferon-Induced Helicase
IFIH1 viruses medicine.medical_treatment Molecular Sequence Data Down-Regulation Genome Viral Viral Nonstructural Proteins Mitochondrion Biology Virus Replication Cell Line DEAD-box RNA Helicases Viral Proteins medicine Animals Humans Amino Acid Sequence Adaptor Proteins Signal Transducing Mitochondrial antiviral-signaling protein Enzyme Precursors NS3 Multidisciplinary Innate immune system Protease biochemical phenomena metabolism and nutrition Biological Sciences Macaca mulatta Virology Cysteine protease Immunity Innate Mitochondria NS2-3 protease Cysteine Endopeptidases Interferon Regulatory Factors RNA Viral Virus Activation Hepatitis A virus IRF3 Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:7253-7258 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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