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NLRX1 mediates MAVS degradation to attenuate hepatitis C virus-induced innate immune response through PCBP2.

NLRX1 mediates MAVS degradation to attenuate hepatitis C virus-induced innate immune response through PCBP2.
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Qin Y, Xue B, Liu C, Wang X, Tian R, Xie Q, Guo M, Li G, Yang D, Zhu H,


Qin Y, Xue B, Liu C, Wang X, Tian R, Xie Q, Guo M, Li G, Yang D, Zhu H, (click to view)

Qin Y, Xue B, Liu C, Wang X, Tian R, Xie Q, Guo M, Li G, Yang D, Zhu H,

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Journal of virology 2017 09 27() pii JVI.01264-17
Abstract

Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. However, attenuation or termination of signaling is also necessary for preventing immune-mediated tissue damage and spontaneous autoimmunity. Here, we identify NLRX1 as a negative regulator for MAVS-mediated signaling pathway during HCV infection. Depletion of NLRX1 enhances HCV-triggered activation of IFN signaling and causes the suppression of HCV propagation in hepatocytes. NLRX1, a HCV-inducible protein, interacts with MAVS and mediates the K48-linked polyubiquitination and the subsequent degradation of MAVS via proteasomal pathway. Moreover, PCBP2 interacts with NLRX1 to participate in NLRX1-induced degradation of MAVS and inhibition of antiviral responses during HCV infection. Mutagenic analyses further revealed that the NOD domain of NLRX1 is essential for NLRX1 to interact with PCBP2 and subsequently induce MAVS degradation. Our study unlocks a key mechanism of fine tuning of innate immunity by which NLRX1 restrains RLRs-MAVS signaling cascade by recruiting PCBP2 to MAVS for inducing MAVS degradation through the proteasomal pathway. NLRX1, a negative regulator of innate immunity, is a pivotal host factor for HCV to establish persistent infection.IMPORTANCE Innate immunity needs to be tightly regulated to maximize antiviral response and minimize immune-mediated pathology. Whereas, the underlying mechanisms are poorly understood. In this study, we report that NLRX1 is a proviral host factor for HCV infection and functions as a negative regulator in HCV-triggered innate immune response. NLRX1 recruits PCBP2 to MAVS and induces the K48-linked polyubiquitination and degradation of MAVS, leading to the negative regulation of IFN signaling pathway and promoting HCV infection. Overall, this study provides intriguing insights into how innate immunity is regulated during viral infection.

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