title: Porcine Reproductive and Respiratory Syndrome Virus nsp1α Inhibits NF-κB Activation by Targeting the Linear Ubiquitin Chain Assembly Complex.
abstract: Linear ubiquitination, a newly discovered posttranslational modification, is catalyzed by the linear ubiquitin chain assembly complex (LUBAC), which is composed of three subunits: one catalytic subunit HOIP and two accessory molecules, HOIL-1L and SHARPIN. Accumulating evidence suggests that linear ubiquitination plays a crucial role in innate immune signaling and especially in the activation of the NF-κB pathway by conjugating linear polyubiquitin chains to NF-κB essential modulator (NEMO, also called IKKγ), the regulatory subunit of the IKK complex. Porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide, is an ideal model to study the host's disordered inflammatory responses after viral infection. Here, we found that LUBAC-induced NF-κB and proinflammatory cytokine expression can be inhibited in the early phase of PRRSV infection. Screening the PRRSV-encoded proteins showed that nonstructural protein 1α (nsp1α) suppresses LUBAC-mediated NF-κB activation and its CTE domain is required for the inhibition. Mechanistically, nsp1α binds to HOIP/HOIL-1L and impairs the interaction between HOIP and SHARPIN, thus reducing the LUBAC-dependent linear ubiquitination of NEMO. Moreover, PRRSV infection also blocks LUBAC complex formation and NEMO linear-ubiquitination, the important step for transducing NF-κB signaling. This unexpected finding demonstrates a previously unrecognized role of PRRSV nsp1α in modulating LUBAC signaling and explains an additional mechanism of immune modulation by PRRSV.
  
  
  OBJECTIVE
  Porcine reproductive and respiratory syndrome (PRRS) is one of the most important veterinary infectious diseases in countries with intensive swine industries. PRRS virus (PRRSV) infection usually suppresses proinflammatory cytokine expression in the early stage of infection, whereas it induces an inflammatory storm in the late stage. However, precisely how the virus is capable of doing so remains obscure. In this study, we found that by blocking the interaction of its catalytic subunit HOIP and accessory molecule SHARPIN, PRRSV can suppress NF-κB signal transduction in the early stage of infection. Our findings not only reveal a novel mechanism evolved by PRRSV to regulate inflammatory responses but also highlight the important role of linear ubiquitination modification during virus infection.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Liurong
authors.initials: L
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Huanchun
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China vet@mail.hzau.edu.cn.|The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019318:Porcine Reproductive and Respiratory Syndrome / Q000378:metabolism* / Q000821:virology*; D019316:Porcine respiratory and reproductive syndrome virus / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D013552:Swine; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D025801:Ubiquitin; D017361:Viral Nonstructural Proteins; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
keywords: inflammation; linear ubiquitin chain assembly complex; nonstructural protein 1α (nsp1α); porcine reproductive and respiratory syndrome virus