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.
Highlights
Since life is originated from the RNA World[1,2,3], it is postulated that double-stranded RNA may be the earliest form of life
We demonstrated that dsCARE mimicking the RIG-I like receptor (RLR) family prohibited viral infection by eliminating infected cells from the innate immune system via programmed cell necrosis or necroptosis, an important innate immune response of mammals uncovered within the last decade
Our data showed that the chimeric RLR receptor was capable of detecting virus-associated double-stranded RNA (dsRNA) and activating necroptosome that consisted of RIP1, RIP3 and mixed lineage kinase domain like (MLKL) in virus-infected cells via lysosomal enzyme cathepsin D in addition to promoting the expression of inflammatory cytokine IL-1β but inactivating the well documented IFN pathway
Summary
Since life is originated from the RNA World[1,2,3], it is postulated that double-stranded RNA (dsRNA) may be the earliest form of life. The RIG-I-like receptors, consisting of the dsRNA binding domain (dsRBD) and the caspase activation and recruitment domain (CARD) represent a family of natural dsRNA-dependent CARD-containing PRRs primarily regulating inflammatory responses and apoptosis during viral infection[7,10,11]. These dsRNA receptors are shown to recruit mitochondrial antiviral-signaling protein (MAVS, known as VISA/Cardif/IPS-1) to activate TANK-binding kinase 1/inducible Iκ B kinase (TBK1/IKKi) and IKK complex[12]. It was possible to manipulate downstream antiviral responses by swapping its CARD with a proper CARD-containing protein
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
