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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

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MS-based identification of AcP10 interaction partners.

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2020-07-24 | PXD011879 | Pride

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2024-03-19 | GSE261399 | GEO

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2020-09-30 | PXD016149 | Pride

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2019-11-02 | GSE138371 | GEO

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2019-03-02 | GSE127713 | GEO

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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.

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