4.8 Article

The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy

期刊

AUTOPHAGY
卷 19, 期 7, 页码 1916-1933

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TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2022.2162798

关键词

Influenza A virus; MAVS; mitophagy; nucleoprotein; TOLLIP

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Mitophagy, a type of autophagy, plays a crucial role in maintaining the stability of functional mitochondria in the cell. This study identified the nucleoprotein (NP) of H1N1 virus as a regulator of mitophagy. The NP-mediated mitophagy leads to the degradation of MAVS, a protein anchored to mitochondria, which then blocks antiviral signaling and promotes virus replication. The interaction between NP, MAVS, and the cargo receptor TOLLIP is required for the NP-mediated mitophagy. Furthermore, a specific mutation in NP significantly reduces virus-induced mitophagy and virus replication in vitro and in vivo. Overall, this study uncovers a novel mechanism in which the NP of influenza virus induces mitophagy to attenuate innate immunity.
Mitophagy is a form of autophagy that plays a key role in maintaining the homeostasis of functional mitochondria in the cell. Viruses have evolved various strategies to manipulate mitophagy to escape host immune responses and promote virus replication. In this study, the nucleoprotein (NP) of H1N1 virus (PR8 strain) was identified as a regulator of mitophagy. We revealed that NP-mediated mitophagy leads to the degradation of the mitochondria-anchored protein MAVS, thereby blocking MAVS-mediated antiviral signaling and promoting virus replication. The NP-mediated mitophagy is dependent on the interaction of NP with MAVS and the cargo receptor TOLLIP. Moreover, Y313 of NP is a key residue for the MAVS-NP interaction and NP-mediated mitophagy. The NPY313F mutation significantly attenuates the virus-induced mitophagy and the virus replication in vitro and in vivo. Taken together, our findings uncover a novel mechanism by which the NP of influenza virus induces mitophagy to attenuate innate immunity.

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