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Gle1 mediates stress granule-dependent survival during chemotoxic stress.

ABSTRACT: Stress granules (SGs) are non-membrane bound organelles that form in response to multiple different stress stimuli, including exposure to sodium arsenite. SGs are postulated to support cells during periods of stress and provide a protective effect, allowing survival. Gle1 is a highly conserved, essential modulator of RNA-dependent DEAD-box proteins that exists as at least two distinct isoforms in human cells. Gle1A is required for proper SG formation, whereas Gle1B functions in mRNA export at the nuclear pore complex. Since Gle1A is required for SG function, we hypothesized that SG-dependent survival responses would also be Gle1-dependent. We describe here an experimental system for quantifying and testing the SG-associated survival response to sodium arsenite stress in HeLa cells. Gle1A was required for the sodium arsenite survival response, and overexpression of Gle1A supported the survival response. Overexpression of the SG-component G3BP also enabled the response. Next, we analyzed whether cells undergoing multiple rounds of stress yield a subpopulation with a higher propensity for SG formation and an increased resistance to undergoing apoptosis. After ten doses of sodium arsenite treatment, cells became resistant to sodium arsenite and to diclofenac sodium (another SG-inducing drug). The sodium arsenite-resistant cells exhibited changes in SG biology and had an increased survival response that was conferred in a paracrine manner. Changes in secreted factors occurred including a significantly lower level of MCP-1, a known regulator of stress granules and stress-induced apoptosis. This study supports models wherein SGs play a role in cell evasion of apoptosis and further reveal Gle1A and SG functions as targets for clinical approaches directed at chemoresistant/refractory cells.

SUBMITTER: Glass L

PROVIDER: S-EPMC6347492 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Gle1 mediates stress granule-dependent survival during chemotoxic stress.

Glass Laura L Wente Susan R SR

Advances in biological regulation 20180918

Stress granules (SGs) are non-membrane bound organelles that form in response to multiple different stress stimuli, including exposure to sodium arsenite. SGs are postulated to support cells during periods of stress and provide a protective effect, allowing survival. Gle1 is a highly conserved, essential modulator of RNA-dependent DEAD-box proteins that exists as at least two distinct isoforms in human cells. Gle1A is required for proper SG formation, whereas Gle1B functions in mRNA export at th ...[more]

PMID: 30262214

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Project description:UnlabelledA hallmark of Ebola virus (EBOV) infection is the formation of viral inclusions in the cytoplasm of infected cells. These viral inclusions contain the EBOV nucleocapsids and are sites of viral replication and nucleocapsid maturation. Although there is growing evidence that viral inclusions create a protected environment that fosters EBOV replication, little is known about their role in the host response to infection. The cellular stress response is an effective antiviral strategy that leads to stress granule (SG) formation and translational arrest mediated by the phosphorylation of a translation initiation factor, the α subunit of eukaryotic initiation factor 2 (eIF2α). Here, we show that selected SG proteins are sequestered within EBOV inclusions, where they form distinct granules that colocalize with viral RNA. These inclusion-bound (IB) granules are functionally and structurally different from canonical SGs. Formation of IB granules does not indicate translational arrest in the infected cells. We further show that EBOV does not induce formation of canonical SGs or eIF2α phosphorylation at any time postinfection but is unable to fully inhibit SG formation induced by different exogenous stressors, including sodium arsenite, heat, and hippuristanol. Despite the sequestration of SG marker proteins into IB granules, canonical SGs are unable to form within inclusions, which we propose might be mediated by a novel function of VP35, which disrupts SG formation. This function is independent of VP35's RNA binding activity. Further studies aim to reveal the mechanism for SG protein sequestration and precise function within inclusions.ImportanceAlthough progress has been made developing antiviral therapeutics and vaccines against the highly pathogenic Ebola virus (EBOV), the cellular mechanisms involved in EBOV infection are still largely unknown. To better understand these intracellular events, we investigated the cellular stress response, an antiviral pathway manipulated by many viruses. We show that EBOV does not induce formation of stress granules (SGs) in infected cells and is therefore unrestricted by their concomitant translational arrest. We identified SG proteins sequestered within viral inclusions, which did not impair protein translation. We further show that EBOV is unable to block SG formation triggered by exogenous stress early in infection. These findings provide insight into potential targets of therapeutic intervention. Additionally, we identified a novel function of the interferon antagonist VP35, which is able to disrupt SG formation.

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Gle1 mediates stress granule-dependent survival during chemotoxic stress.

Publications

Gle1 mediates stress granule-dependent survival during chemotoxic stress.

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