Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication

Abstract

Influenza A virus usurps host signaling factors to regulate its replication. One example is mTOR, a cellular regulator of protein synthesis, growth and motility. While the role of mTORC1 in viral infection has been studied, the mechanisms that induce mTORC1 activation and the substrates regulated by mTORC1 during influenza virus infection have not been established. In addition, the role of mTORC2 during influenza virus infection remains unknown. Here we show that mTORC2 and PDPK1 differentially phosphorylate AKT upon influenza virus infection. PDPK1-mediated phoshorylation of AKT at a distinct site is required for mTORC1 activation by influenza virus. On the other hand, the viral NS1 protein promotes phosphorylation of AKT at a different site via mTORC2, which is an activity dispensable for mTORC1 stimulation but known to regulate apoptosis. Influenza virus HA protein and down-regulation of the mTORC1 inhibitor REDD1 by the virus M2 protein promote mTORC1 activity. Systematic phosphoproteomics analysis performed in cells lacking the mTORC2 component Rictor in the absence or presence of Torin, an inhibitor of both mTORC1 and mTORC2, revealed mTORC1-dependent substrates regulated during infection. Members of pathways that regulate mTORC1 or are regulated by mTORC1 were identified, including constituents of the translation machinery that once activated can promote translation. mTORC1 activation supports viral protein expression and replication. As mTORC1 activation is optimal midway through the virus life cycle, the observed effects on viral protein expression likely support the late stages of influenza virus replication when infected cells undergo significant stress.

Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

“…As reported earlier, Ras-PI3K signaling axis acts as a host-oriented mechanism for viral internalization [40]. Moreover, a recent study has shown that mTORC1 activation supports viral protein expression and replication specifically at later stages of IAV infection when the cell is under significant stress [15]. In the present study, we have also shown that the IAV infection activates N-Ras, which further phosphorylates Akt and activates the downstream mTOR signaling proteins.…”

Metabolic host response and therapeutic approaches to influenza infection

“…The viral hemagglutinin (HA) protein, along with virus replication, can upregulate PDPK1-mediated phosphorylation and activate AKT, which is required for induction of the mTORC1 signaling pathway by the influenza virus. On the other hand, influenza M2 protein is capable of down-regulation of the mTORC1 inhibitor REDD1, thereby enhancing the mTORC1 activation [69]. mTORC1 signaling, in turn, promotes c-Myc expression at the translational level [70].…”

Role of MAPK/MNK1 signaling in virus replication

“…(Hall, 2008). The high ATP/AMP ratio promotes and activates mTORC1, which leads to the dissociation of eIF4E from 4E-BP, ultimately resulting in enhanced protein synthesis (Brett et al, 2014), to support virus replication (Kuss-Duerkop et al, 2017;McNulty et al, 2013;Stohr et al, 2016). Conversely, antiviral role of mTORC1 has been demonstrated in CHIKV where virus has evolved a mechanism to bypass mTORC1 inhibition via MNK1/eIF4E mediated translation (Joubert et al, 2015) (Fig.…”

“…This global inhibition of cellular protein synthesis aids in immune evasion (Ersahin et al, 2015;Porta et al, 2014). For example, influenza virus (Kuss-Duerkop et al, 2017), vaccinia virus and cowpox virus (Soares et al, 2009) activate mTORC2-Akt signaling which play a critical role in survivalbility at late stage of viral infection. However, in a study, DENV polyprotein was found to suppress only host cell translation at the level of translation initiation whereas viral protein synthesis remained unaffected.…”