Small molecule ISRIB suppresses the integrated stress response within a defined window of activation
Authors: Martijn A Langereis
Aditya A Anand
Peter Walter
Frank J M van Kuppeveld
Huib H Rabouw
Linda J Visser
Raoul J de Groot
Journal: Proceedings of the National Academy of Sciences of the United States of America (2019)
Discipline: Multidisciplinary
Keywords: ISRIB; P-eIF2; eIF2B; integrated stress response.
Affiliations: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands., Howard Hughes Medical Institute, University of California, San Francisco, CA 94143., Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143., Howard Hughes Medical Institute, University of California, San Francisco, CA 94143;  ., Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;  .

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. 

Retracted: No

PubPeer comments:
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 #1 This looks like a job for Contrast-Enhancement Man! ![file] To repeat Leydigiopsis Brevirostris s comment: Same background in the TNF-alpha, COX-2 and iNOS slices. Same background in the MCP-1 and MIP-2 slices. Background in IL-12 slice overlaps with that of MCP-1 and MIP-2. In the IL-12 slice, there is a vertical discontinuity between Lane 1 and the others. ![file] , 
 #1 and #2 The concerns raised are very compelling. It would be appreciated if the authors could reply and a) provide original images if they are still available, or b) indicate that they are not. *** False color ![file] ,