tetano
Editor, Senior Moderator
J Virol. 2018 Dec 12. pii: JVI.01984-18. doi: 10.1128/JVI.01984-18. [Epub ahead of print]
[h=1]Autophagy benefits the replication of influenza A virus in vitro.[/h] Wang R[SUP]1,[/SUP][SUP]2[/SUP], Zhu Y[SUP]1,[/SUP][SUP]2[/SUP], Zhao J[SUP]1,[/SUP][SUP]2[/SUP], Ren C[SUP]1,[/SUP][SUP]2[/SUP], Li P[SUP]1,[/SUP][SUP]2[/SUP], Chen H[SUP]1,[/SUP][SUP]2[/SUP], Jin M[SUP]1,[/SUP][SUP]2[/SUP], Zhou H[SUP]3,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A virus (IAV) infection could induce autophagosome accumulation. However, the impact of the autophagy machinery on IAV infection remains controversial. Herein, we showed that induction of cellular autophagy by starvation or rapamycin treatment increases the progeny virus production, while devastation of autophagy using siRNA and pharmacological inhibitor reduces the progeny virus production. Further studies revealed that alteration of autophagy significantly affects the early stages of the virus life cycle or viral RNA synthesis. Importantly, we demonstrated that both IAV M2 and NP proteins overexpression alone lead to the lipidation of LC3 to LC3-II, and a redistribution of LC3 from the cytosol to punctate vesicles indicative of authentic autophagosomes. Intriguingly, both M2 and NP colocalize and interact with LC3 puncta during M2 or NP transfection alone and IAV infection, leading to the increase of the vRNP export and infectious viral particles formation, indicating that IAV-host autophagy interaction plays a critical role in regulating IAV replication. We showed that NP and M2 induce the AKT-mTOR-dependent autophagy pathway and the increase of HSP90AA1 expression. Finally, our studies provided evidence that IAV replication needs an autophagy pathway to enhance viral RNA synthesis via the interaction of PB2 and HSP90AA1 by modulating the HSP90AA1 expression and AKT-mTOR signaling pathway in host cells. Collectively, our studies uncover a new mechanism that NP and M2-mediated autophagy function in different stages of virus replication into pathogenicity of influenza A virus.IMPORTANCE Autophagy impacts the replication cycle of many viruses. However, the role of autophagy machinery on IAV replication remains unclear. Therefore, we explored the detailed mechanisms utilized by IAV to promote its replication. We demonstrated that IAV NP and M2 mediated autophagy promotes IAV replication by regulating AKT-mTOR signaling pathway and HSP90AA1 expression: the interaction of PB2 and HSP90AA1 results in the increase of viral RNA synthesis first, the binding of NP to LC3 favors the vRNP export ever since but later the interaction of M2 and LC3 leads to increase of the production of infectious viral particles, thus accelerating the viral progeny production. These findings improve understanding of IAV pathogenicity in host cells.
PMID: 30541828 DOI: 10.1128/JVI.01984-18
[h=1]Autophagy benefits the replication of influenza A virus in vitro.[/h] Wang R[SUP]1,[/SUP][SUP]2[/SUP], Zhu Y[SUP]1,[/SUP][SUP]2[/SUP], Zhao J[SUP]1,[/SUP][SUP]2[/SUP], Ren C[SUP]1,[/SUP][SUP]2[/SUP], Li P[SUP]1,[/SUP][SUP]2[/SUP], Chen H[SUP]1,[/SUP][SUP]2[/SUP], Jin M[SUP]1,[/SUP][SUP]2[/SUP], Zhou H[SUP]3,[/SUP][SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza A virus (IAV) infection could induce autophagosome accumulation. However, the impact of the autophagy machinery on IAV infection remains controversial. Herein, we showed that induction of cellular autophagy by starvation or rapamycin treatment increases the progeny virus production, while devastation of autophagy using siRNA and pharmacological inhibitor reduces the progeny virus production. Further studies revealed that alteration of autophagy significantly affects the early stages of the virus life cycle or viral RNA synthesis. Importantly, we demonstrated that both IAV M2 and NP proteins overexpression alone lead to the lipidation of LC3 to LC3-II, and a redistribution of LC3 from the cytosol to punctate vesicles indicative of authentic autophagosomes. Intriguingly, both M2 and NP colocalize and interact with LC3 puncta during M2 or NP transfection alone and IAV infection, leading to the increase of the vRNP export and infectious viral particles formation, indicating that IAV-host autophagy interaction plays a critical role in regulating IAV replication. We showed that NP and M2 induce the AKT-mTOR-dependent autophagy pathway and the increase of HSP90AA1 expression. Finally, our studies provided evidence that IAV replication needs an autophagy pathway to enhance viral RNA synthesis via the interaction of PB2 and HSP90AA1 by modulating the HSP90AA1 expression and AKT-mTOR signaling pathway in host cells. Collectively, our studies uncover a new mechanism that NP and M2-mediated autophagy function in different stages of virus replication into pathogenicity of influenza A virus.IMPORTANCE Autophagy impacts the replication cycle of many viruses. However, the role of autophagy machinery on IAV replication remains unclear. Therefore, we explored the detailed mechanisms utilized by IAV to promote its replication. We demonstrated that IAV NP and M2 mediated autophagy promotes IAV replication by regulating AKT-mTOR signaling pathway and HSP90AA1 expression: the interaction of PB2 and HSP90AA1 results in the increase of viral RNA synthesis first, the binding of NP to LC3 favors the vRNP export ever since but later the interaction of M2 and LC3 leads to increase of the production of infectious viral particles, thus accelerating the viral progeny production. These findings improve understanding of IAV pathogenicity in host cells.
PMID: 30541828 DOI: 10.1128/JVI.01984-18