University of British Columbia
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I'm a PhD Candidate at the University of British Columbia with an interest in the interplay between virus and host. I strive to understand how our immune system challenges viruses and how viruses have evolved to hijack and evade that very same system. My current research projects focus on RIG-I like receptors and the signalling pathways involved in the sensing of viral RN
Cleavage of 14-3-3ε by the enteroviral 3Cpro dampens RIG-I mediated antiviral signaling
Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. RIG-I is an antiviral factor that senses viral RNA and signals downstream via MAVS, inducing IFN-β transcription. 14-3-3ε is a key component of the RIG-I translocon complex, which is necessary for RIG-I translocation to the mitochondria to activate MAVS. The importance of 14-3-3ε in host signaling is exemplified by several viral mechanisms that counteract 14-3-3ε function in the RIG-I translocon, though the exact role of 14-3-3ε in the translocon is not fully understood. Using an N-terminomics-based approach, we identified 14-3-3ε as a substrate of the poliovirus (PV) and coxsackievirus B3 (CVB3) 3C protease. 14-3-3ε, among other 14-3-3 family proteins, are cleaved during infection. 3Cpro cleaves 14-3-3ε at Q236, resulting in a stable N-terminal fragment of 27.0kDa. Expression of the N-terminal fragment, but not the wild-type 14-3-3ε protein, in 14-3-3ε siRNA-depleted A549 cells impairs poly(I:C)-mediated IFN-β production. In poly(I:C) stimulated cells, the N-terminal fragment does not interact with RIG-I by immunoprecipitation assays. Moreover, overexpression of the N-terminal fragment impaired IFN-β production and RIG-I translocation to mitochondria, suggesting a dominant-negative effect. Scanning alanine mutagenesis of the C-terminal intrinsically-disordered domain identified key residues for RIG-I signaling. Finally, preliminary data shows that expression of the N-terminal domain of 14-3-3ε in H1N1 influenza-infected cells similarly dampens IFN-β production. We propose a model whereby strategic enterovirus 3Cpro-mediated cleavage of 14-3-3ε disrupts critical interactions necessary for the formation of the RIG-I translocon, contributing to evasion of the host antiviral response.