Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation

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Abstract

Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2a phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPPlR15-type regulatory subunit. An unbiased search for additional conserved components of the PPP1R15-PP1 phosphatase identified monomeric G-actin. Like PP1, G-actin associated with the functional core of PPP1R15 family members and G-actin depletion, by the marine toxin jasplakinolide, destabilised the endogenous PPP1R15A-PP1 complex. The abundance of the ternary PPPlR15-PPl-G-actin complex was responsive to global changes in the polymeric status of actin, as was its eIF2a-directed phosphatase activity, while localised G-actin depletion at sites enriched for PPP1R15 enhanced eIF2a phosphorylation and the downstream ISR. G-actin’s role as a stabilizer of the PPPlR15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR.

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Chambers, J. E., Dalton, L. E., Clarke, H. J., Malzer, E., Dominicus, C. S., Patel, V., … Marciniak, S. J. (2015). Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. ELife, 2015(4). https://doi.org/10.7554/eLife.04872

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