The Transcriptional Response to Oxidative Stress is Independent of Stress-Granule Formation
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ABSTRACT:
PROVIDER: PRJNA739161 | ENA |
REPOSITORIES: ENA
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Project description:We characterized oxidative-stress-induced transcriptional changes in Drosophila S2 cells and assessed how these were altered under conditions that disrupted stress granule (SG) assembly. Sodium-arsenite stress for 3 hours resulted predominantly in the induction or upregulation of stress-responsive mRNAs whose levels peaked during cell recovery after stress cessation. RNAi-mediated knock down of the conserved G3BP1/ Rasputin protein inhibited stress-granule assembly. However, this disruption had no significant effect on the stress-induced transcriptional response.
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Project description:Ribonucleoprotein (RNP) granules are non-membrane bound organelles thought to assemble by protein-protein interactions of RNA-binding proteins. We present evidence that a wide variety of RNAs self-assemble in vitro into either liquid-liquid phase separations or more stable assembles, referred to as RNA tangles. Self-assembly in vitro is affected by RNA length, ionic conditions, and sequence. Remarkably, self-assembly of yeast RNA in vitro under physiological salt mimics the composition of mRNAs within yeast stress granules. This suggests that the biophysical principles that drive RNA self-assembly in vitro contribute to determining the stress granule transcriptome. Consistent with RNA self-assembly contributing to RNP granule formation, an excess of purified RNA injected into C. elegans syncytium coalesces into droplet-like assemblies. We suggest that diverse RNA-RNA interactions in trans contribute to RNP granule formation and may explain the prevalence of large RNA-protein assemblies in eukaryotic cells.
2017-05-23 | GSE99170 | GEO
Project description:Stress granule formation is a part of cellular homeostatic responses, with prototypical inducers being viral infections, heat shock and oxidative damage. Here we show that lysosomal damage is a previously unappreciated robust inducer of stress granule formation interlinked with mTOR inactivation during lysosomal damage. We find the two processes to be coordinated by a non-autophagy function of mammalian Atg8 proteins (mAtg8s). Stress granules were induced in response to biochemical damage and diverse lysosome damaging biological agents including SARS-CoV-2 ORF3a, Mycobacterium tuberculosis and protopathic tau. Proteomic analyses of purified lysosomes subjected to biochemical damage revealed recruitment to lysosomes of a network of stress granule proteins, including G3BP1 and NUFIP2. G3BP1 and NUFIP2 contributed to inactivation of mTOR during lysosomal damage via the Ragulator-RagA/B system. Lysosomal damage recruited a subset of mAtg8s commonly related to autophagy but also known to associate with other stressed or remodeling membranes. The GABARAP subset of mAtg8s interacted with G3BP1 and NUFIP2 and were required for NUFIP2 and G3BP1 recruitment to the damaged lysosomes. GABARAPs acted as a switch between the utilization of G3BP1 and NUFIP2 in stress granule formation vs. their role in mTOR inactivation. We furthermore found that mAtg8s lipidation, referred herein as Atg8ylation to distinguish it from its conventional implication in autophagy, but not the canonical autophagy factors ATG13, FIP200, and ATG9A, favored mTOR inactivation during lysosomal damage vs. the stress granule formation. Thus, cells utilize Atg8ylation as a response to membrane stress for specific outcomes beyond the process of autophagy, which include the coordinated stress granule formation and mTOR inactivation during lysosomal damage
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Project description:Stress granule and inflammasome assembly determine contrasting fates of stressed cells. FAM69C is a brain-enriched kinase associated with neurodegenerative diseases, but its biological functions are still largely unknown. Here we show that FAM69C plays an important role in the regulation of stress responses through promoting stress granule assembly and suppressing inflammasome activation. In response to ATP, a common inflammasome activator, mouse primary microglia, and BV-2 cells form stress granules. FAM69C deficiency hastens inflammasome activation in mouse microglia, which is accompanied by inhibited stress granule assembly. FAM69C promotes the assembly of stress granules and halts protein translation under stress. Aged Fam69c knockout mice show increased neuroinflammation and ASC specks formation. We further find that FAM69C physically phosphorylates eIF2α and promotes stress granule assembly. Our data reveal that FAM69C promotes stress granule assembly under stress and suppresses inflammasome formation in microglia, suggesting that FAM69C may be a potential therapeutic target for neurodegenerative diseases.
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Project description:We investigated the sub-cellular architecture of Stress Granules in the context of glucose starvation. In order to uncover transient and peripheral Stress Granule interactors, we optimized the proximity-dependent biotinylation (BioID) approach for use in yeast. This approach allowed us to visualize Stress Granule formation while simultaneously inducing the biotinylation of SG components and nearby proteins in live cells. We used two independent Stress Granule components Pub1 and Pab1.
2020-03-23 | PXD016988 | Pride
Project description:Stress granules are dynamic cytoplasmic ribonucleoprotein granules that assemble in response to cellular stress. Aberrant formation of stress granules has been linked to neurodegenerative diseases. However, the molecular mechanisms underlying the initiation of stress granules remain elusive. Here we report that the brain-enriched protein kinase FAM69C promotes stress granule assembly through phosphorylation of eukaryotic translation initiation factor 2 (eIF2α). FAM69C physically interacts with eIF2α and functions as a stress-specific kinase for eIF2α, leading to stress-induced protein translation arrest and stress granule assembly. Primary microglia derived from Fam69c knockout mice exhibit aberrant stress granule assembly in response to oxidative stress and ATP. Defective stress granule assembly in microglia correlates with the formation of ASC specks and NLRP3 inflammasome activation, whereas induction of stress granule precludes inflammasome formation. Consistently, increased NLRP3 levels, caspase-1 cleavage and Il18 expression corroborate microglia-associated neuroinflammation in aged Fam69c knockout mice. Our study demonstrates that FAM69C is critical for stress granule assembly and suggests its role in the regulation of microglia function.
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Project description:Cells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded protein and viral stress responses, whether and how SGs contribute to stress-induced transcription have not been rigorously examined. To address this, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Oxidative stress for 3 h predominantly resulted in induction or up-regulation of stress-responsive mRNAs whose levels peaked during recovery after stress cessation. The stress transcriptome is enriched in mRNAs coding for chaperones including HSP70s, small heat shock proteins, glutathione transferases, and several noncoding RNAs. Oxidative stress also induced cytoplasmic SGs that disassembled 3 h after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/Rasputin protein inhibited SG assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus SG assembly and stress-induced gene expression alterations appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.
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