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

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 an stabilizer of the PPP1R15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR.

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Author details

  1. Joseph E Chambers

    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. Lucy E Dalton

    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Hanna J Clarke

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Elke Malzer

    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  5. Caia S Dominicus

    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  6. Vruti Patel

    Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  7. Greg Moorhead

    Department of Biological Sciences, University of Calgary, Calgary, Canada
    Competing interests
    No competing interests declared.
  8. David Ron

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    David Ron, Reviewing editor, eLife.
  9. Stefan J Marciniak

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    sjm20@cam.ac.uk
    Competing interests
    No competing interests declared.

Copyright

© 2015, Chambers et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joseph E Chambers
  2. Lucy E Dalton
  3. Hanna J Clarke
  4. Elke Malzer
  5. Caia S Dominicus
  6. Vruti Patel
  7. Greg Moorhead
  8. David Ron
  9. Stefan J Marciniak
(2015)
Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation
eLife 4:e04872.
https://doi.org/10.7554/eLife.04872

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https://doi.org/10.7554/eLife.04872

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