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Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.

Publication ,  Journal Article
Reid, DW; Tay, ASL; Sundaram, JR; Lee, ICJ; Chen, Q; George, SE; Nicchitta, CV; Shenolikar, S
Published in: Mol Cell Biol
July 1, 2016

Phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation in stressed cells. While phosphorylated eIF2α (P-eIF2α) attenuates global protein synthesis, mRNAs encoding stress proteins are more efficiently translated. Two eIF2α phosphatases, containing GADD34 and CReP, catalyze P-eIF2α dephosphorylation. The current view of GADD34, whose transcription is stress induced, is that it functions in a feedback loop to resolve cell stress. In contrast, CReP, which is constitutively expressed, controls basal P-eIF2α levels in unstressed cells. Our studies show that GADD34 drives substantial changes in mRNA translation in unstressed cells, particularly targeting the secretome. Following activation of the unfolded protein response (UPR), rapid translation of GADD34 mRNA occurs and GADD34 is essential for UPR progression. In the absence of GADD34, eIF2α phosphorylation is persistently enhanced and the UPR translational program is significantly attenuated. This "stalled" UPR is relieved by the subsequent activation of compensatory mechanisms that include AKT-mediated suppression of PKR-like kinase (PERK) and increased expression of CReP mRNA, partially restoring protein synthesis. Our studies highlight the coordinate regulation of UPR by the GADD34- and CReP-containing eIF2α phosphatases to control cell viability.

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Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

July 1, 2016

Volume

36

Issue

13

Start / End Page

1868 / 1880

Location

United States

Related Subject Headings

  • Unfolded Protein Response
  • Protein Phosphatase 1
  • Protein Biosynthesis
  • Phosphorylation
  • Mice
  • Membrane Proteins
  • Fibroblasts
  • Eukaryotic Initiation Factor-2
  • Developmental Biology
  • Cells, Cultured
 

Citation

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Reid, D. W., Tay, A. S. L., Sundaram, J. R., Lee, I. C. J., Chen, Q., George, S. E., … Shenolikar, S. (2016). Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Mol Cell Biol, 36(13), 1868–1880. https://doi.org/10.1128/MCB.00190-16
Reid, David W., Angeline S. L. Tay, Jeyapriya R. Sundaram, Irene C. J. Lee, Qiang Chen, Simi E. George, Christopher V. Nicchitta, and Shirish Shenolikar. “Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.Mol Cell Biol 36, no. 13 (July 1, 2016): 1868–80. https://doi.org/10.1128/MCB.00190-16.
Reid DW, Tay ASL, Sundaram JR, Lee ICJ, Chen Q, George SE, et al. Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Mol Cell Biol. 2016 Jul 1;36(13):1868–80.
Reid, David W., et al. “Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.Mol Cell Biol, vol. 36, no. 13, July 2016, pp. 1868–80. Pubmed, doi:10.1128/MCB.00190-16.
Reid DW, Tay ASL, Sundaram JR, Lee ICJ, Chen Q, George SE, Nicchitta CV, Shenolikar S. Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Mol Cell Biol. 2016 Jul 1;36(13):1868–1880.

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

July 1, 2016

Volume

36

Issue

13

Start / End Page

1868 / 1880

Location

United States

Related Subject Headings

  • Unfolded Protein Response
  • Protein Phosphatase 1
  • Protein Biosynthesis
  • Phosphorylation
  • Mice
  • Membrane Proteins
  • Fibroblasts
  • Eukaryotic Initiation Factor-2
  • Developmental Biology
  • Cells, Cultured