Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation.
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Date
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Publisher
eLife
https://doi.org/10.7554/elife.04872
https://doi.org/10.7554/elife.04872
Abstract
Description
Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2α phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPP1R15-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 PPP1R15-PP1-G-actin complex was responsive to global changes in the polymeric status of actin, as was its eIF2α-directed phosphatase activity, while localised G-actin depletion at sites enriched for PPP1R15 enhanced eIF2α phosphorylation and the downstream ISR. G-actin's role as a stabilizer of the PPP1R15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR.
This work was funded by the Medical Research Council (UK) (MRC Ref G1002610) and a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (CIMR, Wellcome 100140). SJM holds a Senior Clinical Research Fellowship from the Medical Research Council (MRC Ref G1002610). DR is a Wellcome Trust Principal Research Fellow (Wellcome 084812/Z/08/Z). The June Hancock Mesothelioma Research Fund funded LED (JH09-2); the British Lung Foundation funded HJC (APHD11-4); CD is a member of the CIMR PhD programme funded by the Wellcome Trust; and VP holds a Diabetes UK Arthur and Sadie Pethybridge PhD Studentship.
This is the final published version. It first appeared at http://elifesciences.org/content/4/e04872.
This work was funded by the Medical Research Council (UK) (MRC Ref G1002610) and a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (CIMR, Wellcome 100140). SJM holds a Senior Clinical Research Fellowship from the Medical Research Council (MRC Ref G1002610). DR is a Wellcome Trust Principal Research Fellow (Wellcome 084812/Z/08/Z). The June Hancock Mesothelioma Research Fund funded LED (JH09-2); the British Lung Foundation funded HJC (APHD11-4); CD is a member of the CIMR PhD programme funded by the Wellcome Trust; and VP holds a Diabetes UK Arthur and Sadie Pethybridge PhD Studentship.
This is the final published version. It first appeared at http://elifesciences.org/content/4/e04872.
Keywords
CReP, D. melanogaster, GADD34, PPP1R15A, PPP1R15B, actin, biochemistry, cell biology, human, integrated stress response, mouse, Actins, Amino Acid Sequence, Animals, Conserved Sequence, Depsipeptides, Drosophila melanogaster, Eukaryotic Initiation Factor-2, HEK293 Cells, Humans, Mice, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Phosphatase 1, Stress, Physiological