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.
CITATION STYLE
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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