title: Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Nsp4 Cleaves VISA to Impair Antiviral Responses Mediated by RIG-I-like Receptors.
abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most significant etiological agents in the swine industry worldwide. It has been reported that PRRSV infection can modulate host immune responses, and innate immune evasion is thought to play a vital role in PRRSV pathogenesis. In this study, we demonstrated that highly pathogenic PRRSV (HP-PRRSV) infection specifically down-regulated virus-induced signaling adaptor (VISA), a unique adaptor molecule that is essential for retinoic acid induced gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) signal transduction. Moreover, we verified that nsp4 inhibited IRF3 activation induced by signaling molecules, including RIG-I, MDA5, VISA, and TBK1, but not IRF3. Subsequently, we demonstrated that HP-PRRSV nsp4 down-regulated VISA and suppressed type I IFN induction. Importantly, VISA was cleaved by nsp4 and released from mitochondrial membrane, which interrupted the downstream signaling of VISA. However, catalytically inactive mutant of nsp4 abolished its ability to cleave VISA. Interestingly, nsp4 of typical PRRSV strain CH-1a had no effect on VISA. Taken together, these findings reveal a strategy evolved by HP-PRRSV to counteract anti-viral innate immune signaling, which complements the known PRRSV-mediated immune-evasion mechanisms.
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Yinping
authors.initials: Y
authors.lastname: Du
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Yihao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Department of Basic Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States.
authors.forename: Jishu
authors.initials: J
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Agrobiotechnology, Beijing 100193, China.|Ministry of Agriculture Key Laboratory of Soil Microbiology, Beijing 100193, China.|Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Feng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D015536:Down-Regulation; D057131:Immune Evasion; D007370:Interferon Type I / Q000378:metabolism; D019316:Porcine respiratory and reproductive syndrome virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D013552:Swine; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D017361:Viral Nonstructural Proteins; D000071457:DEAD Box Protein 58