Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes

Mazzon, Michela; Castro, Cecilia; Thaa, Bastian; Liu, Lifeng; Mutso, Margit; Liu, Xiang; Mahalingam, Suresh; Griffin, Julian L.; Marsh, Mark; McInerney, Gerald M.

doi:10.1371/journal.ppat.1006835

Cited by 53 publications

(68 citation statements)

References 39 publications

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“…These latter substrates all play a role in cell metabolism. Treatment of infected cells with wortmannin, a specific PI3K inhibitor, reduces but does not eliminate phosphorylation of AKT, PFK2, AS160 and ACL [12,15]. This suggests that SFV-induced AKT hyperactivation is mediated by PI3K-dependent and independent mechanisms.…”

Section: Figure 2 In Semliki Forest Virus (Sfv) and Ross River Virusmentioning

confidence: 98%

“…Both SFV and RRV have been shown to very strongly activate the PI3K-AKT-mTOR pathway, via the presence of YXXM motifs in the C-terminal HVD of nsP3 (Y369-E370-P371-M372 for SFV, and Y356-E357-T358-M359 for RRV) [12] (Figure 2). YXXM motifs are known activators of class 1A PI3Ks [13,14] and, after localisation to the PM in nascent viral RNA replication complexes, the YXXM motifs of SFV and RRV nsP3 bind to one or both of the SH2 domains of p85, thereby releasing the enzymatic p110 subunit, leading to activation of AKT [12]. Strikingly, the hyperactivation of the pathway even occurs when cells are starved of amino acids and growth factors prior to infection.…”

Section: Sfv and Rrv Hyperactivate The Pi3k-akt-mtor Pathway And Downmentioning

confidence: 99%

“…SFV infection leads to the induction of strong phosphorylation of AKT and two downstream targets of mTORC1, S6 and 4E-BP1 [15]. Furthermore, it induces phosphorylation of the AKT substrates phosphofructokinase 2 (PFK2), Rab GTPase-activating protein AS160 (or TBC1D4) and ATP citrate lyase (ACL) [12]. These latter substrates all play a role in cell metabolism.…”

Section: Figure 2 In Semliki Forest Virus (Sfv) and Ross River Virusmentioning

confidence: 99%

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Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Huizen

McInerney

2020

Cells

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Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, there are no vaccines or antiviral therapies for any alphavirus. Several Old World alphaviruses, including Semliki Forest virus, Ross River virus and chikungunya virus, activate or hyperactivate the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in vertebrate cells, potentially influencing many cellular processes, including survival, proliferation, metabolism and autophagy. Inhibition of PI3K or AKT inhibits replication of several alphaviruses either in vitro or in vivo, indicating the importance for viral replication. In this review, we discuss what is known about the mechanism(s) of activation of the pathway during infection and describe those effects of PI3K-AKT activation which could be of advantage to the alphaviruses. Such knowledge may be useful for the identification and development of therapies.Cells 2020, 9, 970 2 of 12 complex mTORC1. AKT signalling leads to the activation of mTORC1, which promotes cell growth by inducing lipid biogenesis through activation of the transcription factors SREBP1 and PPARγ and by promoting protein synthesis by activating the S6 kinase (S6K) and by inactivating the translational inhibitor 4E-BP1. mTORC1 also inhibits autophagy by blocking ULK1 [6]. The serine/threonine kinase glycogen synthase kinase 3 (GSK3) is another multifunctional target of AKT. Through phosphorylation, active GSK3 inhibits most of its substrates. Upon phosphorylation by AKT, GSK3 itself is inhibited and thereby the downstream targets are positively regulated. These targets include the prosurvival BCL-2 family member MCL-1 and the transcription factor c-Myc, which is required for expression of many genes involved in proliferation. Other GSK3-targets, such as glycogen synthase, are involved in (regulation of) cellular metabolism [7]. The third multifunctional target of AKT are the forkhead box O (FoxO) transcription factors. Phosphorylation of FoxO transcription factors by AKT leads to acute translocation out of the nucleus. Thus, AKT signalling suppresses the expression of FoxO targets. These include targets involved in the induction of apoptosis, cell-cycle arrest, catabolic metabolism and growth inhibition. Thus, PI3K-AKT signalling via these multifunctional targets promotes cell survival, growth and proliferation and steers cellular metabolism towards anabolism.

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Section: Figure 2 In Semliki Forest Virus (Sfv) and Ross River Virusmentioning

confidence: 98%

Section: Sfv and Rrv Hyperactivate The Pi3k-akt-mtor Pathway And Downmentioning

confidence: 99%

Section: Figure 2 In Semliki Forest Virus (Sfv) and Ross River Virusmentioning

confidence: 99%

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Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Huizen

McInerney

2020

Cells

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“…Alphavirus nsP3 has three domains: a phosphorylated C-terminal unstructured hypervariable domain, a zinc-binding alphavirus unique domain and an N-terminal macrodomain (MD). The hypervariable domain interacts with multiple cellular proteins important for virus replication (13)(14)(15)(16)(17)(18), and the zinc-binding domain has a role in the synthesis of viral RNA (19)(20)(21)(22). The highly conserved MD consists of a central beta sheet surrounded by four to six helices, a protein fold that exists in all kingdoms of life, including a few families of plus-strand RNA viruses (23)(24)(25)(26)(27).…”

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confidence: 99%

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Abraham

McPherson

Dasovich

et al. 2020

mBio

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Macrodomain (MD), a highly conserved protein fold present in a subset of plus-strand RNA viruses, binds to and hydrolyzes ADP-ribose (ADPr) from ADPribosylated proteins. ADPr-binding by the alphavirus nonstructural protein 3 (nsP3) MD is necessary for the initiation of virus replication in neural cells, whereas hydrolase activity facilitates replication complex amplification. To determine the importance of these activities for pathogenesis of alphavirus encephalomyelitis, mutations were introduced into the nsP3 MD of Sindbis virus (SINV), and the effects on ADPr binding and hydrolase activities, virus replication, immune responses, and disease were assessed. Elimination of ADPr-binding and hydrolase activities (G32E) severely impaired in vitro replication of SINV in neural cells and in vivo replication in the central nervous systems of 2-week-old mice with reversion to wild type (WT) (G) or selection of a less compromising change (S) during replication. SINVs with decreased binding and hydrolase activities (G32S and G32A) or with hydrolase deficiency combined with better ADPr-binding (Y114A) were less virulent than WT virus. Compared to the WT, the G32S virus replicated less well in both the brain and spinal cord, induced similar innate responses, and caused less severe disease with full recovery of survivors, whereas the Y114A virus replicated well, induced higher expression of interferon-stimulated and NF-B-induced genes, and was cleared more slowly from the spinal cord with persistent paralysis in survivors. Therefore, MD function was important for neural cell replication both in vitro and in vivo and determined the outcome from alphavirus encephalomyelitis in mice. IMPORTANCE Viral encephalomyelitis is an important cause of long-term disability, as well as acute fatal disease. Identifying viral determinants of outcome helps in assessing disease severity and developing new treatments. Mosquito-borne alphaviruses infect neurons and cause fatal disease in mice. The highly conserved macrodomain of nonstructural protein 3 binds and can remove ADP-ribose (ADPr) from ADPribosylated proteins. To determine the importance of these functions for virulence, recombinant mutant viruses were produced. If macrodomain mutations eliminated ADPr-binding or hydrolase activity, viruses did not grow. If the binding and hydrolase activities were impaired, the viruses grew less well than the wild-type virus, induced similar innate responses, and caused less severe disease, and most of the infected mice recovered. If binding was improved, but hydrolase activity was decreased, the virus replicated well and induced greater innate responses than did the WT, but clearance from the nervous system was impaired, and mice remained paralyzed. Therefore, macrodomain function determined the outcome of alphavirus encephalomyelitis. Citation Abraham R, McPherson RL, Dasovich M, Badiee M, Leung AKL, Griffin DE. 2020. Both ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain affect neurovirulence in mice. mBio 11:e03253-1...

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“…A549 cells (ATCC CCL-185) were cultured in Ham’s F-12 Nutrient Mixture with GlutaMAX (F12, Gibco), supplemented with 10% (v/v) fetal bovine serum (FBS, Gibco). Semliki Forest virus (SFV)_Zs-Green (a kind gift of Giuseppe Balistreri, University of Helsinki, described in [86]) was expanded and titrated by plaque assay on BHK-21 cells [87]. Zika virus (ZIKV) was expanded and titrated by immunofocus assay on Vero cells.…”

Section: Methodsmentioning

confidence: 99%

Comparative analysis reveals adaptive evolution of bat IFITMs and a novel antiviral determinant

Benfield

MacKenzie

Ritzefeld

et al. 2019

Preprint

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doi: bioRxiv preprint 65 required for the antiviral activity of both IFITM3 and IFITM1 [9]. The subcellular localization of 66 IFITMs is a key determinant of their antiviral profile. When expressed singly, IFITM3 and IFITM2 67 preferentially localize to early and late endosomes and lysosomes, and restrict viruses that enter via 68 these endo-lysosomal compartments. In contrast, IFITM1 primarily localizes at the cell surface and 69 can restrict viruses that enter through the plasma membrane [11-14]. Indeed, mutants of IFITM3 70 that lack an N-terminal endocytic sorting motif 20 YEML 23 localize to the plasma membrane and lose 71 their ability to inhibit influenza A virus (IAV), alphavirus and coronavirus infection by endosomal 72 routes [14-18]. 73 74 Studies focusing on IFITM3 restriction of IAV and Semliki Forest Virus (SFV) indicate that virus 75 internalization is unaffected by IFITM3 expression and, for SFV at least, the viral envelope 76 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/737841 doi: bioRxiv preprint 109 knockout mice show enhanced morbidity after infection with IAV, alphaviruses and flaviviruses [33-110 .

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Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes

Cited by 53 publications

References 39 publications

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Comparative analysis reveals adaptive evolution of bat IFITMs and a novel antiviral determinant

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