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: Wei Wang, Wei-Hua Wang, Kazem M Azadzoi, Ning Su, Peng Dai, Jianbin Sun, Qin Wang, Ping Liang, Wentao Zhang, Xiaoying Lei, Zhen Yan, Jing-Hua Yang
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 22550 (Mar 03 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26935990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AGFG1 protein, human
• IL1B protein, human
• Interleukin-1beta
• Nuclear Pore Complex Proteins
• RNA, Double-Stranded
• RNA, Viral
• RNA-Binding Proteins
• Receptors, Cell Surface
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Cell Death (immunology)
• HEK293 Cells
• Humans
• Immunity, Innate (immunology)
• Interleukin-1beta (immunology)
• Nuclear Pore Complex Proteins (immunology)
• RNA Viruses (immunology)
• RNA, Double-Stranded (immunology)
• RNA, Viral (immunology)
• RNA-Binding Proteins (immunology)
• Receptor-Interacting Protein Serine-Threonine Kinases (immunology)
• Receptors, Cell Surface (immunology)