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


Type

Article

Change log

Authors

Chambers, Joseph E 
Dalton, Lucy E 
Clarke, Hanna J 
Malzer, Elke 
Dominicus, Caia S 

Abstract

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.

Description

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

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

4

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Wellcome Trust (084812/Z/08/Z)
Medical Research Council (G1002610)
Medical Research Council (MR/M010392/1)
Medical Research Council (G0601840)
Wellcome Trust (100140/Z/12/Z)
Diabetes UK (None)
Worldwide Cancer Research (None)
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.