Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2α

By I. Novoa, Huiqing Zeng, H. Harding, D. Ron. Journal of Cell Biology, 2001

1,448 citations recorded by the source corpus.

Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on serine 51 integrates general translation repression with activation of stress-inducible genes such as ATF4, CHOP, and BiP in the unfolded protein response. We sought to identify new genes active in this phospho-eIF2α–dependent signaling pathway by screening a library of recombinant retroviruses for clones that inhibit the expression of a CHOP::GFP reporter. A retrovirus encoding the COOH terminus of growth arrest and DNA damage gene (GADD)34, also known as MYD116 (Fornace, A.J., D.W. Neibert, M.C. Hollander, J.D. Luethy, M. Papathanasiou, J. Fragoli, and N.J. Holbrook. 1989. Mol. Cell. Biol. 9:4196–4203; Lord K.A., B. Hoffman-Lieberman, and D.A. Lieberman. 1990. Nucleic Acid Res. 18:2823), was isolated and found to attenuate CHOP (also known as GADD153) activation by both protein malfolding in the endoplasmic reticulum, and amino acid deprivation. Despite normal activity of the cognate stress-inducible eIF2α kinases PERK (also known as PEK) and GCN2, phospho-eIF2α levels were markedly diminished in GADD34-overexpressing cells. GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2α in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2α and blocked attenuation of CHOP by GADD34. Expression of GADD34 is stress dependent, and was absent in PERK−/− and GCN2−/− cells. These findings implicate GADD34-mediated dephosphorylation of eIF2α in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d1f32feb4d7d101d414cd53f06c03b5043618cf9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. R. Kaufman
2. D. Ron
3. C. Hetz
4. G. Hotamışlıgil
5. Peter Walter
6. H. Harding
7. John Calvin Reed
8. Junying Yuan

In Molecular Biology

1. R. Kaufman
2. D. Ron
3. C. Hetz
4. H. Harding
5. Peter Walter
6. G. Hotamışlıgil
7. Guido Kroemer
8. John Calvin Reed

Citations in the corpus

• The role for endoplasmic reticulum stress in diabetes mellitus. (2008, background): “eIF2 dephosphorylation (95), and perhaps also by up-”
• The eIF2α kinases: their structures and functions (2013, neutral): “This relief of translational repression is required for the transcriptional program of the UPR [140], but also functions to allow polypeptides to enter the already-stressed ER, thus exacerbating the ER stress [139].”
• Endoplasmic Reticulum Stress in Liver Disease (2010, background): “CHOP upregulates the expression of GADD34, which complexes with protein phosphatase 1 (PP1c) to target dephosphorylation of eIF2a, thus forming a negative feedback loop [96].”
• Mechanisms of pre‐apoptotic calreticulin exposure in immunogenic cell death (2009, background): “MTX, OXP and UVC induced the rapid (within 4 h or less) expression of GADD34, a protein that is usually induced by ER stressors (Novoa et al, 2001).”
• Translational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2 (2004, background): “GADD34 was detected with an antiserum directed to the N terminus of the mouse protein raised in our lab ( 30 ).”
• The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, background): “The PERK–CHOP signalling branch stimulates the dephosphorylation of eIF2α through a feedback loop that is mediated by the upregulation of GADD34, which positively regulates a phosphatase complex involving protein phosphatase 1C (PP1C), allowing protein synthesis to resum”
• Endoplasmic reticulum stress sensing in the unfolded protein response. (2013, background): “GADD34 encodes the regulatory subunit of the protein phosphatase PP1C complex that dephosphorylates eIF2a (Novoa et al. 2001), comprising a negative feedback loop to reverse the translational attenuation mediated by PERK.”
• Initiation and execution of lipotoxic ER stress in pancreatic β-cells (2008, background): “This late decrease might be due to GADD34 induction, downstream of ATF4 and CHOP, and consequent proteinphosphatase-1-mediated dephosphorylation of eIF2α (Cnop et al., 2007a; Novoa et al., 2001).”
• CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. (2004, methodology): “The PERK eukaryotic initiation factor 2 kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.”
• Functional diversity of protein phosphatase-1, a cellular economizer and reset button. (2004, background): “5, a protein encoded for by the Herpes simplex virus-1 genome, is structurally related to the PP1 binding COOH terminus of GADD34.”