About: Small molecule ISRIB suppresses the integrated stress response within a defined window of activation

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About: Small molecule ISRIB suppresses the integrated stress response within a defined window of activation Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Small molecule ISRIB suppresses the integrated stress response within a defined window of activation
Creator	Walter, Peter Langereis, Martijn Rabouw, Huib Anand, Aditya De Groot, Raoul Van Kuppeveld, Frank Visser, Linda
Source	Medline; PMC
abstract	Activation of the integrated stress response (ISR) by a variety of stresses triggers phosphorylation of the α-subunit of translation initiation factor eIF2. P-eIF2α inhibits eIF2B, the guanine nucleotide exchange factor that recycles inactive eIF2•GDP to active eIF2•GTP. eIF2 phosphorylation thereby represses translation. Persistent activation of the ISR has been linked to the development of several neurological disorders, and modulation of the ISR promises new therapeutic strategies. Recently, a small-molecule ISR inhibitor (ISRIB) was identified that rescues translation in the presence of P-eIF2α by facilitating the assembly of more active eIF2B. ISRIB enhances cognitive memory processes and has therapeutic effects in brain-injured mice without displaying overt side effects. While using ISRIB to investigate the ISR in picornavirus-infected cells, we observed that ISRIB rescued translation early in infection when P-eIF2α levels were low, but not late in infection when P-eIF2α levels were high. By treating cells with varying concentrations of poly(I:C) or arsenite to induce the ISR, we provide additional proof that ISRIB is unable to inhibit the ISR when intracellular P-eIF2α concentrations exceed a critical threshold level. Together, our data demonstrate that the effects of pharmacological activation of eIF2B are tuned by P-eIF2α concentration. Thus, ISRIB can mitigate undesirable outcomes of low-level ISR activation that may manifest neurological disease but leaves the cytoprotective effects of acute ISR activation intact. The insensitivity of cells to ISRIB during acute ISR may explain why ISRIB does not cause overt toxic side effects in vivo.
has issue date	2019-02-05(xsd:dateTime)
bibo:doi	10.1073/pnas.1815767116
bibo:pmid	30674674
has license	cc-by-nc-nd
sha1sum (hex)	6fe5c74868af62cfacb629af957915de0b094af9
schema:url	https://doi.org/10.1073/pnas.1815767116
resource representing a document's title	Small molecule ISRIB suppresses the integrated stress response within a defined window of activation
has PubMed Central identifier	PMC6369741
has PubMed identifier	30674674
schema:publication	Proc Natl Acad Sci U S A
resource representing a document's body	covid:6fe5c74868af62cfacb629af957915de0b094af9#body_text
is schema:about of	named entity 'WINDOW' named entity 'TO INHIBIT' named entity '80%' named entity 'LEVEL' named entity 'VARIETY' named entity 'DATA' named entity 'MITIGATE' named entity 'PROVIDE' named entity 'INACTIVE' named entity 'ARSENITE' named entity 'THERAPEUTIC' named entity 'RECENTLY' named entity 'MICE' named entity 'INFECTION' named entity '28I' named entity 'LEAVES' named entity 'PROOF' named entity 'STRATEGIES' named entity 'MODULATION' named entity 'EFFECTS' named entity 'mitigate' named entity 'inhibit' named entity 'provide' named entity 'early' named entity 'eIF2' named entity 'eIF2B' named entity 'processes' named entity 'investigate' named entity 'active' named entity 'cells' covid:arg/6fe5c74868af62cfacb629af957915de0b094af9 named entity 'ISR' named entity 'PRESENCE OF' named entity 'COGNITIVE' named entity 'INTACT' named entity 'IDENTIFIED' named entity 'NEW' named entity 'SMALL MOLECULE' named entity 'ADDITIONAL' named entity 'CYTOPROTECTIVE' named entity 'FACILITATING' named entity 'GUANINE NUCLEOTIDE EXCHANGE FACTOR' named entity 'ACTIVE' named entity 'CAUSE' named entity 'ACTIVATION' named entity 'OUTCOMES' named entity 'PHOSPHORYLATION' named entity 'STRESS RESPONSE' named entity 'SUPPRESSES' named entity 'INDUCE' named entity 'ASSEMBLY' named entity 'USING' named entity 'MOLECULE' named entity 'CELLS' named entity 'PHARMACOLOGICAL' named entity 'SUBUNIT' named entity 'HIGH' named entity 'LOW' named entity 'EARLY' named entity 'TREATING' named entity 'TO INVESTIGATE' named entity 'ACUTE' named entity 'INFECTED' named entity 'DOES NOT' named entity 'NEUROLOGICAL DISEASE' named entity 'TRIGGERS' named entity 'OBSERVED' named entity 'STRESSES' named entity 'CONCENTRATIONS' named entity 'EIF2B' named entity 'DISPLAYING' named entity 'DEFINED' named entity 'NEUROLOGICAL DISORDERS' named entity 'DEVELOPMENT' named entity 'OVERT'

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