title: Viral degradasome hijacks mitochondria to suppress innate immunity.
abstract: The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named "NS-degradasome" (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity.
authors.affiliation: Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
authors.forename: Ramansu
authors.initials: R
authors.lastname: Goswami
authors.forename: Tanmay
authors.initials: T
authors.lastname: Majumdar
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Dhar
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Sudip K
authors.initials: SK
authors.lastname: Bandyopadhyay
authors.forename: Valentina
authors.initials: V
authors.lastname: Verbovetskaya
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Sailen
authors.initials: S
authors.lastname: Barik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D017361:Viral Nonstructural Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; D007370:Interferon Type I; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D015739:Nocodazole; D034741:RNA, Small Interfering; D050795:STAT2 Transcription Factor; D017361:Viral Nonstructural Proteins; C512612:MAVS protein, mouse; C470018:MFN2 protein, human; C470017:Mfn1 protein, human