Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses

Berlanga, Juan José; Ventoso, Iván; Harding, Heather P.; Deng, Jing; Ron, David; Sonenberg, Nahum; Carrasco, Luís; Haro, César de

doi:10.1038/sj.emboj.7601073

Cited by 186 publications

(194 citation statements)

References 41 publications

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“…3B), indicating that S6Ks positively control VSV propagation. Consistent with published reports (28,29), at early times after infection, WT MEFs were remarkably resistant to low amounts of VSV (MOI of 1), which might be a result of the genetic background of the MEFs (30). However, at higher MOIs (Fig.…”

Section: Resultssupporting

confidence: 91%

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alain

Lun

Martineau

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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121

108

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Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV ΔM51 ), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV ΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV ΔM51 .innate antiviral immunity | malignant gliomas | mTORC1 | oncolytic viruses M alignant gliomas (MGs) are by far the most frequent, aggressive, and lethal primary brain tumor variants (1, 2). Patients with MGs have a median survival time of approximately 1 y and respond poorly to most available therapeutic modalities (3-5). Thus, more effective treatments are needed.Recent evidence implicates the PI3K/mammalian target of rapamycin (mTOR) signaling pathway as one of the main oncogenic signaling pathways whose deregulation may underlie gliomagenesis (6, 7). mTOR exists in two complexes: mTOR complex 1 (mTORC1), which is sensitive to the drug rapamycin and regulates mRNA translation, and mTORC2, which is rapamycininsensitive and regulates the organization of the actin cytoskeleton (reviewed in refs. 8-10). mTORC1 stimulates type I IFN production via phosphorylation of its target proteins 4E-BPs and S6K1/2 (11). Evidence for the critical role of the mTORC1 signaling pathway in innate immunity emerged from the findings that the mTORC1 inhibitor rapamycin suppresses type I IFN in plasmacytoid dendritic cells (pDCs), which are the major producers of systemic type I IFN (12). In addition, genetic deletion of the mTOR downstream target S6K1/2 leads to impaired type I IFN response (see Results). In contrast, we recently found that the lack of the translational repressors 4E-BP1/2 leads to enhanced type I IFN production (13).Oncogenic transformation is associated with a deficient type I IFN response, which constitutes the first line of defense against virus infection (14,15). Oncolytic viruses are studied as effective anticancer agents because they exploit this selective defect (16)(17)(18)(19). One of the best characterized oncolytic viruses, whose replication is extremely sensitive to the inhibition by IFN, is vesicular stomatitis virus (VSV) (20). However, there are several reasons that limit the use of oncolytic viruses for the treatment of MGs. First, some MGs exhibit a robust type I I...

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Section: Resultssupporting

confidence: 91%

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alain

Lun

Martineau

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

108

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“…5A to C). A recent report has indicated that SB RNA can activate GCN2 when added to cell lysates (2). In cells deficient in each of the eIF2␣ kinases, IFN-␣/␤-mediated inhibition of SB reporter translation was similar to or greater than that observed with PKR Ϫ/Ϫ MEFs.…”

Section: Translation Of Sb and Other Cap-dependent Virus Mrnas Is Inhmentioning

confidence: 81%

Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism

Tesfay

Yin

Gardner

et al. 2008

J Virol

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The alpha/beta interferon (IFN-␣/␤) response is critical for host protection against disseminated replication of many viruses, primarily due to the transcriptional upregulation of genes encoding antiviral proteins. Previously, we determined that infection of mice with Sindbis virus (SB) could be converted from asymptomatic to rapidly fatal by elimination of this response (K. Pathogenesis studies with mice deficient in receptors for alpha/beta interferon (IFN-␣/␤) and IFN-␥ have indicated that IFN-mediated innate responses are vital for the protection of mammals from infections caused by diverse virus types, e.g., lymphocytic choriomeningitis virus (4, 50), Theiler's virus (14), influenza virus (17), measles virus (32), vesicular stomatitis virus (48), and several alphaviruses, including Semliki Forest virus (23, 33), Sindbis virus (SB) (41, 42), and Venezuelan equine encephalitis virus (VEEV) (52). Our results with SB indicate that antiviral activities upregulated by IFN-␣/␤ signaling so severely restrict replication of this apathogenic virus in adult mice that it is virtually undetectable, and disease is completely prevented. However, in the absence of a functional IFN-␣/␤ system, adult mice succumb rapidly to fatal SB disease primarily as a result of systemic infection of macrophages and dendritic cells (DCs) (41). The mechanisms through which the IFN response controls alphavirus replication have not been elucidated (8,43,44). Our results have shown that PKR, but not RNase L, plays an early role in limiting virus replication in DCs; however, IFN-␣/␤ signaling in PKR-deficient animals (PKR Ϫ/Ϫ ) can protect them from fatal SB infection and any manifestations of disease. Furthermore, IFN-mediated protection of DCs or murine embryo fibroblast (MEF) cultures derived from PKR Ϫ/Ϫ mice is as potent as in control cultures (44), and virus replication in these cultures is inhibited very early after infection (43).DThe canonical IFN-␣/␤ signaling pathway involves interaction with the heterodimeric IFN-␣/␤ receptor (IFNAR1 and IFNAR2 subunits), activation of Jak1 and Tyk2 kinases, and phosphorylation and heterodimerization of the STAT1 and STAT2 transcription factors. STAT1/2 heterodimers associate with IRF9, forming the ISGF3 complex which translocates to the nucleus and binds to IFN-stimulated response elements, resulting in transcriptional upregulation of genes, some of which possess antiviral activity. The IFN-␣/␤-upregulated antiviral responses have been thought to primarily involve activation of PKR and 2Ј-5Ј oligoadenylate synthetase (2Ј-5Ј OAS) by double-stranded RNA (dsRNA). PKR-mediated antiviral effects have been attributed to phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) and consequent inhibition of host cell and viral translation initiation. In addition, activated PKR plays a role in apoptosis of infected cells (see, for example, reference 54). The IFN-inducible 2Ј-5Ј OAS binds dsRNA and synthesizes 2Ј-5Ј-linked oligoadenylates that activate constitutive RNase L to cleave host and vi...

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“…3,4 The effects of GCN2 activation were initially described to modulate processes related to protein metabolism or amino acid transport. However, recent studies have demonstrated the role played by GCN2 in other cellular responses, such as sensitivity to RNA viral infection 5 or T-cell differentiation. 6 Although GCN2 is typically activated by amino acid deprivation, UV exposure 7,8 or high levels of urea 9 can also lead to GCN2 activation.…”

mentioning

confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

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General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

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Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses

Cited by 186 publications

References 41 publications

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

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