Adapting the Stress Response: Viral Subversion of the mTOR Signaling Pathway

Abstract

The mammalian target of rapamycin (mTOR) is a central regulator of gene expression, translation and various metabolic processes. Multiple extracellular (growth factors) and intracellular (energy status) molecular signals as well as a variety of stressors are integrated into the mTOR pathway. Viral infection is a significant stress that can activate, reduce or even suppress the mTOR signaling pathway. Consequently, viruses have evolved a plethora of different mechanisms to attack and co-opt the mTOR pathway in order to make the host cell a hospitable environment for replication. A more comprehensive knowledge of different viral interactions may provide fruitful targets for new antiviral drugs.

Keywords: 4EBP1; Akt; PI3K; autophagy; mTOR; virus.

Figure 1

Schematic overview of viruses that subvert the PI3K/Akt/mTOR signaling pathway. External signals, such as growth factors, insulin and cytokines, activate phosphatidylinositol 3-kinase (PI3K) through receptor-mediated binding, which leads to phosphorylation of PIP₂ into PIP₃. mTORC1 is activated via a PI3K-dependent mechanism by Vaccinia virus (VACV), Epstein Barr virus (EBV), Kaposi’s sarcoma herpes virus (KSHV), Adenovirus (ADV), influenza A virus (IAV) and West Nile virus (WNV). Evidence suggests that simian virus 40 (SV40) phosphorylates Akt/mTOR potentially through PI3K. PIP₃ recruits Akt to the plasma membrane whereby it is phosphorylated and activated by PDK1. Varicella zoster virus (VZV), Semliki Forest virus (SFV) and human cytomegalovirus (HCMV) are known to activate Akt by increasing phosphorylation, while vesicular stomatitis virus (VSV) and rift valley fever virus (RVFV) attenuate Akt signaling. Subsequently, activated Akt phosphorylates the negative regulator TSC2 (tuberous sclerosis protein 2), which results in the dissociation of the TSC complex (TSC1 and TSC2). Human papillomavirus (HPV) and HCMV activate mTORC1 by inhibiting or causing the degradation of TSC2, respectively. The activity of Akt is mimicked by herpes simplex virus type 1 (HSV-1), which causes the phosphorylation of TSC2. ADV, SV40 and HPV have dual activities and stimulate mTORC1 by blocking PP2A. Rheb (Ras homolog enriched in brain), in its GTP-loaded state, activates mTORC1, while TSC2 acts to inactivate mTORC1 by hydrolyzing Rheb-GTP to Rheb-GDP. Activation of mTORC1 enables continued protein synthesis and suppresses autophagy. Respiratory syncytial virus (RSV) and human immunodeficiency virus type 1 (HIV-1) have been shown to activate mTOR although the point at which these viruses attack the signaling pathway is unknown. Solid lines indicate the PI3K/Akt/mTOR signaling pathway. Dashed lines indicate clearly identified and wavy dashed lines represent ill-defined points at which viruses subvert the pathway.

Figure 2

Downstream targets of mTORC1. Amino acid availability is transduced to mTORC1 directly by the small GTPase heterodimers RagA/RagC and RagB/RagD, a process that, together with the Ragulator complex, occurs at the lysosome surface. Human cytomegalovirus (HCMV) redistributes mTORC1 to a perinuclear localization in a dynein-dependent but Rag GTPase-independent mechanism. Andes virus (ANDV) modulates mTOR signaling at lysosomes and necessitates Rheb, RagA/B and LAMTOR1. The mTORC1 substrate, 4EBP1, is a negative regulator of mRNA translation initiation that binds to eIF4E to inhibit the formation of the eIF4F complex, which is made up of eIF4A, eIF4E and eIF4G. Phosphorylated 4EBP1 disassociates from eIF4E and frees it up to bind eIF4G, eIF3 and eIF4A to initiate cap-dependent translation. Chikungunya virus (CHIKV) increases the binding affinity of eIF4E to capped mRNA by increasing its phosphorylation. Merkel cell polyomavirus (MCV) causes CDK1-induced hyperphosphorylation of 4EBP1 to promote cap-dependent protein synthesis. Hepatitis C virus (HCV) interferes at multiple points in the pathway including activation of mTOR, enhanced eIF4F complex loading on mRNA and upregulation of internal ribosome entry site translation by associating with eIF4E and the 40S ribosome. Vaccinia virus (VACV) and Herpes simplex virus type 1 (HSV-1) are known to induce the degradation of 4EBP1 and affect the eIF4F complex. Solid lines indicate the PI3K/Akt/mTOR signaling pathway. Dashed lines indicate clearly identified and wavy dashed lines represent ill-defined points at which viruses subvert the pathway.