title: Hepatitis C virus NS3-4A inhibits the peroxisomal MAVS-dependent antiviral signalling response.
abstract: Hepatitis C virus (HCV) is the cause of one of the most prevalent viral infections worldwide. Upon infection, the HCV genome activates the RIG-I-MAVS signalling pathway leading to the production of direct antiviral effectors which prevent important steps in viral propagation. MAVS localizes at peroxisomes and mitochondria and coordinate the activation of an effective antiviral response: peroxisomal MAVS is responsible for a rapid but short-termed antiviral response, while the mitochondrial MAVS is associated with the activation of a stable response with delayed kinetics. The HCV NS3-4A protease was shown to specifically cleave the mitochondrial MAVS, inhibiting the downstream response. In this study, we have analysed whether HCV NS3-4A is also able to cleave the peroxisomal MAVS and whether this would have any effect on the cellular antiviral response. We show that NS3-4A is indeed able to specifically cleave this protein and release it into the cytosol, a mechanism that seems to occur at a similar kinetic rate as the cleavage of the mitochondrial MAVS. Under these conditions, RIG-I-like receptor (RLR) signalling from peroxisomes is blocked and antiviral gene expression is inhibited. Our results also show that NS3-4A is able to localize at peroxisomes in the absence of MAVS. However, mutation studies have shown that this localization pattern is preferred in the presence of a fully cleavable MAVS. These findings present evidence of a viral evasion strategy that disrupts RLR signalling on peroxisomes and provide an excellent example of how a single viral evasion strategy can block innate immune signalling from different organelles.
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Ana R
authors: AR
authors: Ferreira
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Ana C
authors: AC
authors: Magalhães
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Fátima
authors: F
authors: Camões
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Ana
authors: A
authors: Gouveia
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Marta
authors: M
authors: Vieira
authors: Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors: Jonathan C
authors: JC
authors: Kagan
authors: Department of Medical Sciences, Institute for Biomedicine -iBiMED- and Department of Biology, University of Aveiro, Aveiro, Portugal.
authors: Daniela
authors: http://orcid.org/0000-0003-3397-0460
authors: D
authors: Ribeiro
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D009154:Mutation; D020675:Peroxisomes / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D059748:Proteolysis; D015398:Signal Transduction / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D017361:Viral Nonstructural Proteins; C512612:MAVS protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus
keywords: Hepatitis C virus; MAVS; NS3-4A; peroxisomes