UV damage induces G3BP1-dependent stress granule formation that is not driven by translation arrest via mTOR inhibition

Shan, Ying; Khaperskyy, Denys A.

doi:10.1101/2020.04.29.068585

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…Nevertheless, all discovered multifunctional RBPs are ubiquitously expressed across human tissues, suggesting that these proteins are major players in RNA transcriptional and translational regulation, contributing to both global and cell-line or tissue-specific manifestations. For instance, this appears to be the case for G3BP1 - a known multi-functional RBP that can selectively compartmentalize specific sets of mRNAs to stress granules, in order to reprogram mRNA translation under certain global stress conditions (Matsuki et al, 2013; Ying & Khaperskyy, 2021; Sahoo et al, 2018), as well as tissue-specific contexts such as atrial fibrillation in heart (Dong et al, 2019). Additionally, G3BP1 plays an important role in DNA/RNA unwinding (Costa et al, 1999) and binds to specific RNA stem-loop structures to trigger mRNA degradation (Fischer et al, 2020), which is essential for maternal mRNA clearance (Laver et al, 2020)).…”

Section: Discussionmentioning

confidence: 99%

Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

Schneider-Lunitz

Ruiz-Orera

Hübner

et al. 2021

Preprint

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RNA-binding proteins (RBPs) are key regulators of RNA metabolism. Many RBPs possess uncharacterized RNA-binding domains and localize to multiple subcellular compartments, suggesting their involvement in multiple biological processes. We searched for such multifunctionality within a set of 143 RBPs by integrating experimentally validated target genes with the transcriptomes and translatomes of 80 human hearts. This revealed that RBP abundance is predictive of the extent of target regulation in vivo, leading us to newly associate 27 RBPs with translational control. Amongst those were several splicing factors, of which the muscle specific RBM20 modulated target translation rates through switches in isoform production. For 21 RBPs, we newly observed dual regulatory effects impacting both mRNA levels and translation rates, albeit for virtually independent sets of target genes. We highlight a subset, including G3BP1, PUM1, UCHL5, and DDX3X, where dual regulation is achieved by differential affinity for targets of distinct length and functionality. Strikingly, in a manner very similar to DDX3X, the known splicing factors EFTUD2 and PRPF8 selectively influence target translation rates depending on 5' UTR structure. Our results indicate unanticipated complexity of protein-RNA interactions at consecutive stages of gene expression and implicate multiple core splicing factors as key regulators of translational output.

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Section: Discussionmentioning

confidence: 99%

Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

Schneider-Lunitz

Ruiz-Orera

Hübner

et al. 2021

Preprint

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Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Dolliver

Kleer

Bui-Marinos

et al. 2022

Preprint

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Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the highly pathogenic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress (e.g. sodium arsenite treatment). Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV-2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear retention of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in infection compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

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Stress granules dynamics: benefits in cancer

Lee

Namkoong

2022

BMB Rep

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Stress granules (SGs) are stress-induced subcellular compartments, which carry out a particular function to cope with stress. These granules protect cells from stress-related damage and cell death through dynamic sequestration of numerous ribonucleoproteins (RNPs) and signaling proteins, thereby promoting cell survival under both physiological and pathological condition. During tumorigenesis, cancer cells are repeatedly exposed to diverse stress stimuli from the tumor microenvironment, and the dynamics of SGs is often modulated due to the alteration of gene expression patterns in cancer cells, leading to tumor progression as well as resistance to anticancer treatment. In this mini review, we provide a brief discussion about our current understanding of the fundamental roles of SGs during physiological stress and the effect of dysregulated SGs on cancer cell fitness and cancer therapy. [

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UV damage induces G3BP1-dependent stress granule formation that is not driven by translation arrest via mTOR inhibition

Cited by 3 publications

References 51 publications

Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

Multifunctional RNA-binding proteins influence mRNA abundance and translational efficiency of distinct sets of target genes

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Stress granules dynamics: benefits in cancer

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