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A unique ISR Program Determines Cellular Responses to Chronic Stress

ABSTRACT: Integrated Stress Response (ISR) is a homeostatic mechanism induced by endoplasmic reticulum (ER) stress. With acute/transient ER stress, decreased global protein synthesis and increased uORF mRNA translation are followed by translation normalization. Here, we report a dramatically different response during more physiologically relevant chronic ER stress. This unique ISR program is characterized by persistently elevated uORF mRNA translation and concurrent gene expression reprogramming, which permits simultaneous stress sensing and proteostasis. PERK-dependent switching from eIF4F/eIF2B- to eIF3D/GADD34-regulated translation initiation results in partial but not complete translation recovery, and together with transcriptional reprogramming, selectively bolsters expression of proteins with ER functions. Coordination of these transcriptional and translational changes prevents ER dysfunction and inhibits “foamy cell” development, thus establishing a molecular basis for understanding human diseases associated with ER dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE90070 | GEO | 2018/01/05

SECONDARY ACCESSION(S): PRJNA354374

REPOSITORIES: GEO

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eIF2B-capturing viral protein NSs suppresses the integrated stress response

Project description:Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis revealed that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibited neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.

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MS-based identification of AcP10 interaction partners.

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2020-07-24 | PXD011879 | Pride

Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress

Project description:The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability of PPP1R15A mRNA encoding GADD34. We established that the 3' untranslated region of PPP1R15A mRNA contains an active AU-rich element recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control of PPP1R15A mRNA turnover as a key step in establishing the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.

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eIF3d controls the persistent integrated stress response

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Project description:In response to starvation, cells undergo a metabolic shift to ensure their survival by shutting down protein synthesis and activating catabolic processes, including autophagy, to degrade proteins and recycle nutrients. These processes, however, do require protein synthesis. We asked how this fundamental conflict is resolved. Upon starvation, cells activate the Integrated Stress Response (ISR) and inhibit mammalian target of rapamycin complex 1 (mTORC1). The ISR inhibits protein translation through the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), whereas mTORC1 inhibition induces activation of the transcription factors TFEB/TFE3. We discovered that PPP1R15A (aka GADD34), a member of the protein phosphatase 1 complex (PP1) is a direct and early target of TFEB. GADD34 recruits PP1 to dephosphorylate eIF2 and thus fine-tunes protein synthesis to enable translation of the transcriptional program induced by starvation leading to a sustained autophagic flux.

2020-09-30 | PXD016149 | Pride

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Project description:Down syndrome (DS) is the most common genetic cause of intellectual disability and a major biomedical concern. Despite a general consensus that protein homeostasis is essential for normal brain function, little is known about its role in DS. Here, we show that the integrated stress response (ISR)—a conserved signaling network that maintains proteostasis by controlling protein synthesis—is activated in the brains of DS mice and individuals with DS, leading to reduced translation. Genetic and pharmacological suppression of the ISR, either by inhibiting the ISR-initiating double-stranded RNA-activated protein kinase (PKR) or boosting the function of the eIF2•eIF2B complex, which becomes limiting upon ISR activation, de-repressed translation, reversed enhanced inhibitory synaptic transmission, and rescued the deficits in synaptic plasticity and memory in DS mice. Our findings unveil a crucial role for the ISR in DS pathophysiology and suggest tuning of the ISR as a promising therapeutic intervention for DS.

2019-11-02 | GSE138371 | GEO

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2019-03-02 | GSE127713 | GEO

Transcriptional characterization of the Eif2b5[R191H] loss-of-function mouse model

Project description:The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. We have characterized an eIF2B loss of function (LOF) mouse model, carrying the homozygous Eif2b5[R191H] mutation that is homologous to the Vanishing White Matter Disease (VWMD)-causing human R195H variant. Characterization of previously reported transcript markers in animals 3-4 weeks of age confirmed ISR activation in the brain, but not in heterozygous or wild-type littermates.The robust elevation of ISR markers was further confirmed in bulk brain RNA sequencing analysis of a separate cohort of homozygous mutants and wild-type littermates. Known ATF4 targets feature prominently among the most strongly up-regulated genes in the eIF2B mutant compared to WT littermates.

2023-08-22 | GSE240150 | GEO

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Project description:Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by induction of distinct gene programs tailored to each stress condition. Although the mechanisms that lead to general repression of protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here we show that the noncanonical 5′ cap-binding protein eIF3d is specifically activated in response to metabolic stress, due to loss of CK2-mediated phosphorylation near the eIF3d cap-binding pocket. Activated eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mTOR pathway, and eIF3d-mediated translation adaptation is essential for cell survival during chronic glucose deprivation. Our findings reveal a new mechanism of translation reprogramming engaged in response to metabolic stress.

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