title: Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis.
abstract: Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy.
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Departments of Surgery and Urology, VA Boston Healthcare System, Boston University School of Medicine, Boston 510660, MA, USA.
authors.forename: Kazem M
authors.initials: KM
authors.lastname: Azadzoi
authors.affiliation: Departments of Neurosurgery and Oncology, Xijing and Tangdu Hospital, Xi'an, China.|Cancer Research Center, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Su
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Dai
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lei
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Departments of Surgery and Urology, VA Boston Healthcare System, Boston University School of Medicine, Boston 510660, MA, USA.|Cancer Research Center, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Yang
mesh_terms: D016923:Cell Death / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D028861:Nuclear Pore Complex Proteins / Q000276:immunology; D012328:RNA Viruses / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000276:immunology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology*
chemical_list: C119724:AGFG1 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D028861:Nuclear Pore Complex Proteins; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases