The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway

Abstract

The successful replication of mammalian DNA viruses requires that they gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3'-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Mammalian DNA viruses have evolved various mechanisms to activate this pathway to obtain the benefits of Akt activation, including the maintenance of translation through the activation of mTOR. In addition, viruses must overcome the inhibition of this pathway that results from the activation of cellular stress responses during viral infection. This Review will discuss the range of mechanisms that mammalian DNA viruses use to activate this pathway, as well as the multiple mechanisms these viruses have evolved to circumvent inhibitory stress signalling.

Figure 1. Receptor-mediated activation of phosphatidylinositol 3′-kinase (PI3K) and activation of Akt

The example shown is insulin binding to the insulin receptor, which leads to the phosphorylation of insulin receptor substrates (IRS) that can bind, and thus activate, PI3K. In turn, activated PI3K phosphorylates phosphatidylinositol (PI)-4,5-bisphosphate (PtdIns(4,5)P₂), thereby creating PI-3,4,5-triphosphate (PtdIns(3,4,5)P₃) at the plasma membrane. Both Akt and phosphoinositide-dependent protein kinase 1 (PDK1) can be recruited to the membrane by binding PtdIns(3,4,5)P₃. This positions PDK1 and Akt such that PDK1 can phosphorylate, and thus activate, Akt on threonine 308 (T308). PTEN, phosphatase and tensin homologue.

Figure 2. PI3K–Akt–mTOR signalling

The phosphatidylinositol 3′-kinase–Akt–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway is shown. The points in the pathway that transmit the inhibitory effects of cellular stress signalling (hypoxia, energy deprivation, calcium homeostasis and amino acid deprivation) and drugs (5-amino-4-imidazolecarboxamide ribose (AICAR) and rapamycin) are indicated. The extension of the pathway downstream of mTORC1 shows the effects of mTORC1 on the eukaryotic initiation factor (eIF) 4F cap-binding complex, which initiates cap-dependent translation. 4E-BP, eIF4E binding protein; AMPK, AMP-activated kinase; Mnk1, mitogen-activated protein kinase-interacting kinase 1; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PDK1, phosphoinositide-dependent protein kinase 1; PtdIns(3,4,5)P₃, phosphatidylinositol-3,4,5-triphosphate; PtdIns(4,5)P₂, phosphatidylinositol-4,5-bisphosphate; raptor, regulatory associated protein of TOR; rictor, rapamycin-insensitive companion of mTOR; S6, ribosomal protein S6; S6K, p70S6 kinase; S473, serine 473; T308, threonine 308; TSC, tuberous sclerosis complex.

Figure 3. Mechanisms by which mTORC1 activity controls cap-dependent translation

The eukaryotic initiation factor (eIF) 4F complex consists of: eIF4E, the subunit that binds to the 5′ cap and thus brings the complex to the mRNA; eIF4G, the scaffolding protein to which the other components bind; mitogen-activated protein kinase-interacting kinase 1 (Mnk1), an eIF4E kinase; and eIF4A, an RNA helicase. The functionality of the eIF4F complex relies on the association between eIF4E and eIF4G. However, the binding of 4E-BP to eIF4E displaces eIF4E from eIF4G and the remainder of the complex, and thus inhibits cap-dependent translation. mTOR complex 1 (mTORC1) controls whether or not 4E-BP binds eIF4E by controlling 4E-BP phosphorylation. When mTORC1 is active, under positive growth conditions (a), it phosphorylates 4E-BP, which is therefore unable to bind to eIF4E. Thus, eIF4E is free to bind to eIF4G, which completes the eIF4F complex on the 5′ cap and permits translation to proceed. Under negative growth conditions, for example, during stress or the inhibition of mTORC1 by rapamycin (b), mTORC1 is inactive; 4E-BP therefore becomes hypophosphorylated and binds efficiently to eIF4E, thereby removing it from the eIF4F complex and inhibiting cap-dependent translation.

Figure 4. Summary of the effects of mammalian DNA viruses on the components of the PI3K–Akt–mTOR pathway, the substrates of mTORC1 and the eIF4F complex

The many activating and inhibitory mechanisms that are used by DNA viruses to maintain mTOR complex 1 (mTORC1) activity and cap-dependent translation are summarized. However, it should be noted that these effects might also provide many other physiological changes in the cell that can benefit a productive viral infection and contribute to viral pathogenesis. 4E-BP, eIF4E binding protein; AD, adenovirus; eIF, eukaryotic elongation factor; HCMV, human cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus; Mnk1, mitogen-activated protein kinase-interacting kinase 1; mTOR, mammalian target of rapamycin; MV, myxoma virus; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3′ kinase; PP2A, protein phosphatase 2A; S6, ribosomal protein S6; S6K, p70S6 kinase; ST, small tumour antigen; SV, simian virus 40; TSC, tuberous sclerosis complex; VV, vaccinia virus.