Autophagy is involved in regulating influenza A virus RNA and protein synthesis associated with both modulation of Hsp90 induction and mTOR/p70S6K signaling pathway

Liu, Ge; Zhong, Meigong; Guo, Chaowan; Komatsu, Masaaki; Xu, Jun; Wang, Yifei; Kitazato, Kaio

doi:10.1016/j.biocel.2016.01.012

Cited by 41 publications

(42 citation statements)

References 40 publications

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“…Moreover, NP can physically interact with LC3 in both virus-infected cells and in cells coexpressing LC3; suppressing IAV infection-induced autophagy decreases vRNP export, which suggests that autophagy accelerates vRNP export by colocalizing with LC3 at the perinuclear region and interacting with LC3, thereby promoting IAV replication. Furthermore, HSP90AA1 maintains PI3K/AKT activity by binding to AKT (69), and the AKT-mTOR pathway is crucial for protein synthesis and the regulation of autophagy (66). The IAV polymerase complex consisting of three subunits (PA, PB1, and PB2) is essential for viral RNA replication and transcription (8), and HSP90AA1 has been identified as a host factor to interact with PB2 to promote influenza vRNA synthesis, including nuclear import and assembly of vRNPs (67,68,75).…”

Section: Discussionmentioning

confidence: 99%

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Autophagy Promotes Replication of Influenza A Virus In Vitro

Wang

Zhu

Zhao

et al. 2019

J Virol

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Influenza A virus (IAV) infection could induce autophagosome accumulation. However, the impact of the autophagy machinery on IAV infection remains controversial. Here, we showed that induction of cellular autophagy by starvation or rapamycin treatment increases progeny virus production, while disruption of autophagy using a small interfering RNA (siRNA) and pharmacological inhibitor reduces 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 overexpression of both the IAV M2 and NP proteins alone leads 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 an increase in viral ribonucleoprotein (vRNP) export and infectious viral particle formation, which indicates that the 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 an increase in 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 HSP90AA1 expression and the AKT-mTOR signaling pathway in host cells. Collectively, our studies uncover a new mechanism that NP-and M2-mediated autophagy functions in different stages of virus replication in the pathogenicity of influenza A virus. IMPORTANCE Autophagy impacts the replication cycle of many viruses. However, the role of the autophagy machinery in 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 the AKT-mTOR signaling pathway and HSP90AA1 expression. The interaction of PB2 and HSP90AA1 results in the increase of viral RNA synthesis first; subsequently the binding of NP to LC3 favors vRNP export, and later the interaction of M2 and LC3 leads to an increase in the production of infectious viral particles, thus accelerating viral progeny production. These findings improve our understanding of IAV pathogenicity in host cells.

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Section: Discussionmentioning

confidence: 99%

“…IAV induces autophagy via an AKT-mTOR signaling pathway (61), which is reported to be crucial for protein synthesis (66). IAV induces autophagy via an AKT-mTOR signaling pathway (61), which is reported to be crucial for protein synthesis (66).…”

Section: Inhibition Of Autophagy Decreases Influenza Virus Replicationmentioning

confidence: 99%

Autophagy Promotes Replication of Influenza A Virus In Vitro

Wang

Zhu

Zhao

et al. 2019

J Virol

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“…[47][48][49] Interestingly, the mTOR pathway functions in parallel with Hsp90 in modulating autophagy. [50] Inhibition of both pathways is synergistic in infected cells. The suggested link between these pathways involves viral-induced activation of the Hsp90 client, Akt, which in turn phosphorylates mTOR to facilitate translation of viral mRNA.…”

Section: ]mentioning

confidence: 99%

Drug Repositioning Suggests a Role for the Heat Shock Protein 90 Inhibitor Geldanamycin in Treating COVID-19 Infection

Sultan¹,

Howard²,

Tbakhi³

2020

Preprint

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Drug repositioning offers an unmatched opportunity to offer novel therapeutics to treat SARS family of coronaviruses (SARS-FCoVs); an issue that became extremely urgent with the spreading of a novel virus with potential to threaten the lives of millions of people. Hereby, we analyzed a dataset of patients who presented with SARS during the 2003 outbreak. We established a gene signature that defines differential gene expression in patients who were sick with SARS vs. healthy controls and convalescent patients. We used a robust platform to conduct drug repositioning based on clustered gene expression and pathway enrichment to identify best matching drugs. We identified 55 agents of potential benefit. In most of these drugs we were able to establish a link to previous related research, use as antiviral, or at least a hypothetical role in treating SARS-FCoVs. Most notably, the heat shock protein 90 (hsp90) emerged as a major component that enables viruses to hijack infected cells through the process of autophagy. Almost half of the drugs identified could be linked to hsp90. As such, we propose using hsp90 inhibitors, mainly geldanamycin and its derivatives, to treat COVID-19.

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“…As well as the physiological functions of autophagy, it plays an important role in viral replication [24,25]. For example, influenza A virus and porcine reproductive and respiratory syndrome virus infections can trigger autophagosome formation, but prevent the fusion of lysosomes and autophagosomes, benefitting viral replication through the accumulation of viral RNA and proteins [26,27]. However, herpes simplex virus replication is inhibited by autophagy through EIF2AK2/protein kinase R-dependent autophagic degradation [28], and the replication of zika virus is restricted to mature neurons by autophagy, through its degradation by RELA/NFKB-dependent STING autophagy [29].…”

Section: Introductionmentioning

confidence: 99%

BST2 suppresses porcine epidemic diarrhea virus replication by targeting and degrading virus nucleocapsid protein with selective autophagy

et al. 2019

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Interferon-induced BST2 (bone marrow stromal cell antigen 2) inhibits viral replication by tethering enveloped virions to the cell surface to restrict viral release and by inducing the NFKB-dependent antiviral immune response. However, the mechanism by which BST2 uses the selective autophagy pathway to inhibit viral replication is poorly understood. In this study, we showed that BST2 expression was significantly increased during porcine epidemic diarrhea virus (PEDV) infection of Vero cells by IRF1 targeting its promoter. We also showed that BST2 suppressed PEDV replication by binding and degrading the PEDV-encoded nucleocapsid (N) protein. The downregulation of N protein was blocked by macroautophagy/autophagy inhibitors but not a proteasome inhibitor, implying that the N protein was degraded via the selective autophagy pathway. Both the BST2 and N protein interacted with the E3 ubiquitin ligase MARCHF8/MARCH8 and the cargo receptor CALCOCO2/NDP52, and the ubiquitination of N protein was necessary for the degradation of N mediated by the BST2-MARCHF8 axis. The knockdown of MARCHF8 or ATG5 with small interfering RNAs blocked the selective autophagy pathway, rescued the protein abundance of PEDV N in 293T cells, and prevented the inhibition of PEDV replication by BST2 in Vero cells. Together, our data demonstrate the novel mechanism of BST2-mediated virus restriction, in which BST2 recruits MARCHF8 to catalyze the ubiquitination of the PEDV N protein. The ubiquitinated N protein is then recognized by CALCOCO2/NDP52, which delivers it to autolysosome for degradation through the selective autophagy pathway.

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Autophagy is involved in regulating influenza A virus RNA and protein synthesis associated with both modulation of Hsp90 induction and mTOR/p70S6K signaling pathway

Cited by 41 publications

References 40 publications

Autophagy Promotes Replication of Influenza A Virus In Vitro

Autophagy Promotes Replication of Influenza A Virus In Vitro

Drug Repositioning Suggests a Role for the Heat Shock Protein 90 Inhibitor Geldanamycin in Treating COVID-19 Infection

BST2 suppresses porcine epidemic diarrhea virus replication by targeting and degrading virus nucleocapsid protein with selective autophagy

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