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

Rabouw, Huib H.; Langereis, Martijn A.; Anand, Aditya; Visser, Lenneke de; Groot, Raoul J. de; Walter, Peter; Kuppeveld, Frank J. M. van

doi:10.1073/pnas.1815767116

Cited by 188 publications

(164 citation statements)

References 45 publications

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“…Since the cellular concentrations of eIF2 greatly exceed that of eIF2B, high levels of eIF2 phosphorylation would sequester all decameric eIF2B complexes in an inactive state and eliminate ISRIB's effect. In accordance with these predictions, cell-based assays indicate that high levels of stress abolish ISRIB's ability to suppress the ISR [12,21].…”

Section: Interactions With Eif2 and Phosphorylated Eif2supporting

confidence: 63%

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Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response

Anand

Walter

2019

The FEBS Journal

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The integrated stress response (ISR) regulates protein synthesis under conditions of stress. Phosphorylation of translation initiation factor eIF2 by stress‐sensing kinases converts eIF2 from substrate to competitive inhibitor of its dedicated nucleotide exchange factor, eIF2B, arresting translation. A drug‐like molecule called integrated stress response inhibitor (ISRIB) reverses the effects of eIF2 phosphorylation and restores translation by targeting eIF2B. When administered to mice, ISRIB enhances cognition and limits cognitive decline due to brain injury. To determine ISRIB’s mechanism of action, we solved an atomic structure of ISRIB bound to the human eIF2B decamer. We found that ISRIB acts as a molecular staple, pinning together tetrameric subcomplexes of eIF2B along the assembly path to a fully active, decameric enzyme. In this Structural Snapshot, we discuss ISRIB’s mechanism, its ability to rescue disease mutations in eIF2B and conservation of the enzyme and ISRIB‐binding pocket.

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Section: Interactions With Eif2 and Phosphorylated Eif2supporting

confidence: 63%

“…In accordance with these predictions, cell-based assays indicate that high levels of stress abolish ISRIB's ability to suppress the ISR [12,21]. This new binding mode sequesters the assembled decamer in an inactive state with consequences for ISRIB's activity.…”

Section: Interactions With Eif2 and Phosphorylated Eif2supporting

confidence: 60%

Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response

Anand

Walter

2019

The FEBS Journal

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“…However, this bioinformatic approach resulted in the identification of numerous transcription factor potential binding motifs, including 2 motifs for ATF4, 3 motifs for ATF6, 4 motifs for XBP1, 19 motifs for CHOP, and 36 motifs for TP53. Hence, to further examine whenever miR-34c-5p expression is controlled by one of the UPR pathways, we performed experiments with pharmacological inhibitors of the following UPR braches: 4m8C, a specific IRE1 inhibitor (56); integrated stress response inhibitor, which reverses reversing effects of eIF2-a phosphorylation (57,58); and Ceapin-A7, which prevents ATF6-a signaling (59,60) during Tm and Thp treatment. As shown in Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

miR‐34c‐5p modulates X‐box–binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response

Bartoszewska¹,

Cabaj

Dąbrowski

et al. 2019

FASEB j.

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During endoplasmic reticulum (ER) stress conditions, an adaptive signaling network termed the unfolded protein response (UPR) is activated. The UPR's function is to increase ER protein‐folding capacity in order to attenuate ER stress, restore ER homeostasis, and, most importantly, promote cell survival. X‐box–binding protein 1 (XBP1) is one component of the UPR and is a proadaptive transcription factor that is subject to transcriptional, post‐transcriptional, and post‐translational control. In the present study, we identified a post‐transcriptional mechanism mediated by miR‐34c‐5p that governs the expression of both the spliced (active) and unspliced (latent) forms of XBP1 mRNAs. We showed that miR‐34c‐5p directly attenuates spliced XBP1 (XBP1s) mRNA levels during ER stress and thus regulates the proadaptive component of the UPR that is mediated by XBP1s without interfering with the induction of apoptotic responses.—Bartoszewska, S., Cabaj, A., Dabrowski, M., Collawn, J. F., Bartoszewski, R. miR‐34c‐5p modulates X‐box‐binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response. FASEB J. 33, 11541–11554 (2019). http://www.fasebj.org

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“…induces the transcription of CHOP, which induces apoptosis upon reaching a threshold level (49). Therefore, ISRIB might function to reduce ISR and promote an adaptive response and survival short-term, while being detrimental during the chronic stress (50).…”

Section: Discussionmentioning

confidence: 99%

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

Watanabe

Markov

et al. 2020

Preprint

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Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts.Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.

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

Cited by 188 publications

References 45 publications

Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response

Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response

miR‐34c‐5p modulates X‐box–binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

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