Stress Granules Inhibit Apoptosis by Reducing Reactive Oxygen Species Production

Takahashi, Masahiko; Higuchi, Masakazu; Matsuki, Hideaki; Yoshita, Manami; Ohsawa, Toshiaki; Oie, Masayasu; Fujii, Masahiro

doi:10.1128/mcb.00763-12

Cited by 190 publications

(232 citation statements)

References 27 publications

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“…The truncated form of G3BP1 lacking the NTF2-like N-terminal domain does not induce SGs, as previously observed (14,16). In both single-cycle and multiple-cycle infections, G3BP1 expression caused a potent antiviral effect ranging between 1-and 3-log-unit reduction of virus output compared to the GFP control in all three enteroviruses tested (Fig.…”

Section: G3bp1 and G3bp1-induced Sgs Restrict Enterovirus Infectionsupporting

confidence: 52%

“…Depletion of G3BP1 inhibits SG formation in response to several stressors (10,12,14), and overexpression of G3BP1 nucleates SG formation independently of additional stressors (2,14,15). We previously reported that large G3BP1-induced SGs, but not small granules, are capable of triggering eIF2␣ phosphorylation through PKR, resulting in translational repression (15).…”

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confidence: 99%

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The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Reineke

Lloyd

2015

J Virol

181

189

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Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1-induced SGs are linked to activation of innate immune transcriptional responses through NF-B and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2␣ phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity. IMPORTANCEStress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection. Stress granules (SGs) are macromolecular triage centers for mRNAs that contain translationally silenced messenger RNPs (mRNPs). Stress granules contain many translation initiation factors, 40S ribosomal subunits, mRNAs, and RNA-binding proteins, which form in response to cellular stresses that inhibit protein synthesis (1, 2). Stress responses are induced during virus infection and are countered by viruses to maximize replication efficiency. Indeed, several examples of viral SG disruption and viral subversion of SG proteins have been described (3-6), indicating stress granules may play antiviral roles against these viruses. Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactiv...

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Section: G3bp1 and G3bp1-induced Sgs Restrict Enterovirus Infectionsupporting

confidence: 52%

mentioning

confidence: 99%

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Reineke

Lloyd

2015

J Virol

181

189

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“…However, others have reported that stress granules can form in the presence of H 2 O 2 in an eIF2␣-independent manner (44,92 Stress granule formation reduces the development of reactive oxygen species, thereby inhibiting apoptosis and favoring repair (93). The YB-1 protein has been proposed to play a key role in translation regulation by interacting with quadruplexes.…”

Section: Discussionmentioning

confidence: 99%

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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Cells engage numerous signaling pathways in response to oxidative stress that together repair macromolecular damage or direct the cell toward apoptosis. As a result of DNA damage, mitochondrial DNA or nuclear DNA has been shown to enter the cytoplasm where it binds to "DNA sensors," which in turn initiate signaling cascades. Here we report data that support a novel signaling pathway in response to oxidative stress mediated by specific guanine-rich sequences that can fold into G-quadruplex DNA (G4DNA). In response to oxidative stress, we demonstrate that sequences capable of forming G4DNA appear at increasing levels in the cytoplasm and participate in assembly of stress granules. Identified proteins that bind to endogenous G4DNA in the cytoplasm are known to modulate mRNA translation and participate in stress granule formation. Consistent with these findings, stress granule formation is known to regulate mRNA translation during oxidative stress. We propose a signaling pathway whereby cells can rapidly respond to DNA damage caused by oxidative stress. Guanine-rich sequences that are excised from damaged genomic DNA are proposed to enter the cytoplasm where they can regulate translation through stress granule formation. This newly proposed role for G4DNA provides an additional molecular explanation for why such sequences are prevalent in the human genome.

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“…SYNTHÈSE REVUES la séquestration des protéines pro-oxydantes (comme G3BP1) dans les granules de stress [49]. L'inhibition pharmacologique de HRI pourrait alors, en empêchant la formation des granules de stress suite aux traitements thérapeutiques, favoriser la surproduction des ROS létales, sensibilisant ainsi les tumeurs résistantes à la mort cellulaire.…”

Section: Gfp-hri G3bpunclassified

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

2014

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Stress Granules Inhibit Apoptosis by Reducing Reactive Oxygen Species Production

Cited by 190 publications

References 27 publications

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

The Stress Granule Protein G3BP1 Recruits Protein Kinase R To Promote Multiple Innate Immune Antiviral Responses

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

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