Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD
| Autor: | Daisuke Yamane, Zongdi Feng, Kui Li, Stanley M. Lemon, Lin Qu, Robert E. Lanford, Yuqiong Liang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Gastroenterology and hepatology
medicine.medical_treatment viruses Substrate Specificity 0302 clinical medicine Interferon Luciferases Immune Response lcsh:QH301-705.5 0303 health sciences 3C Viral Proteases Signal transducing adaptor protein virus diseases Hepatitis A Innate Immunity 3. Good health Cysteine Endopeptidases Infectious hepatitis Infectious Diseases RNA Viral Cytokines Medicine 030211 gastroenterology & hepatology Signal transduction medicine.drug Plasmids Signal Transduction Research Article lcsh:Immunologic diseases. Allergy Proteases Immunology Biology Transfection Microbiology Immune Suppression Cell Line 03 medical and health sciences Viral Proteins Virology Genetics medicine Humans Molecular Biology Liver diseases 030304 developmental biology Mitochondrial antiviral-signaling protein Protease Immunity Interferon-beta biochemical phenomena metabolism and nutrition Molecular biology Immunity Innate Toll-Like Receptor 3 NS2-3 protease Adaptor Proteins Vesicular Transport lcsh:Biology (General) TRIF Immune System Parasitology Interferon Regulatory Factor-3 Clinical Immunology Hepatitis A virus lcsh:RC581-607 |
| Zdroj: | PLoS Pathogens, Vol 7, Iss 9, p e1002169 (2011) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Toll-like receptor 3 (TLR3) and cytosolic RIG-I-like helicases (RIG-I and MDA5) sense viral RNAs and activate innate immune signaling pathways that induce expression of interferon (IFN) through specific adaptor proteins, TIR domain-containing adaptor inducing interferon-β (TRIF), and mitochondrial antiviral signaling protein (MAVS), respectively. Previously, we demonstrated that hepatitis A virus (HAV), a unique hepatotropic human picornavirus, disrupts RIG-I/MDA5 signaling by targeting MAVS for cleavage by 3ABC, a precursor of the sole HAV protease, 3Cpro, that is derived by auto-processing of the P3 (3ABCD) segment of the viral polyprotein. Here, we show that HAV also disrupts TLR3 signaling, inhibiting poly(I:C)-stimulated dimerization of IFN regulatory factor 3 (IRF-3), IRF-3 translocation to the nucleus, and IFN-β promoter activation, by targeting TRIF for degradation by a distinct 3ABCD processing intermediate, the 3CD protease-polymerase precursor. TRIF is proteolytically cleaved by 3CD, but not by the mature 3Cpro protease or the 3ABC precursor that degrades MAVS. 3CD-mediated degradation of TRIF depends on both the cysteine protease activity of 3Cpro and downstream 3Dpol sequence, but not 3Dpol polymerase activity. Cleavage occurs at two non-canonical 3Cpro recognition sequences in TRIF, and involves a hierarchical process in which primary cleavage at Gln-554 is a prerequisite for scission at Gln-190. The results of mutational studies indicate that 3Dpol sequence modulates the substrate specificity of the upstream 3Cpro protease when fused to it in cis in 3CD, allowing 3CD to target cleavage sites not normally recognized by 3Cpro. HAV thus disrupts both RIG-I/MDA5 and TLR3 signaling pathways through cleavage of essential adaptor proteins by two distinct protease precursors derived from the common 3ABCD polyprotein processing intermediate. Author Summary While viruses that target the liver often cause lengthy infections with considerable morbidity, there is limited understanding of how they evade host responses. We have studied hepatitis A virus (HAV), an important cause of acute hepatitis in humans. Although HAV infection typically results in hepatic inflammation, there is no disease in the liver during the first weeks of infection despite robust virus replication. This suggests that HAV either fails to stimulate or efficiently evades recognition by host innate immune sensors. Our prior work showed HAV disrupts RIG-I/MDA5 signaling by targeting MAVS, an essential adaptor protein, for degradation by 3ABC, a precursor of the only HAV protease, 3Cpro. Here, we show here that a distinct viral processing intermediate, the 3CD protease-polymerase, disrupts TLR3 signaling by degrading its adaptor protein, TRIF. HAV has evolved a novel strategy to target two different host adaptor proteins with a single protease, using its 3Dpol RNA polymerase to modify the substrate specificity of its 3Cpro protease when fused to it in the 3CD precursor, thus allowing it to target non-canonical 3Cpro recognition sequences in TRIF. This remarkable example of viral adaptation allows the virus to target two different host adaptor proteins with a single viral protease. |
| Databáze: | OpenAIRE |
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