Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official VSports app下载. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

Review
. 2016 Oct;17(10):1374-1395.
doi: 10.15252/embr.201642195. Epub 2016 Sep 14.

The integrated stress response

Karolina Pakos-Zebrucka  1 , Izabela Koryga  1 , Katarzyna Mnich  1 , Mila Ljujic  1 , Afshin Samali  1 , Adrienne M Gorman  2
Affiliations
Review

The integrated stress response

Karolina Pakos-Zebrucka et al. EMBO Rep. 2016 Oct.

Abstract

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli VSports手机版. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress. .

Keywords: activating transcription factor 4; eIF2α kinase; eukaryotic translation initiation factor 2 alpha; integrated stress response V体育安卓版. .

PubMed Disclaimer

"V体育官网" Figures

Figure 1
Figure 1. Integrated stress response signaling
ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2α, the core of ISR. This leads to global attenuation of Cap‐dependent translation while concomitantly initiates the preferential translation of ISR‐specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. It forms homo‐ and heterodimers that bind to DNA targets to control the expression of genes involved in cellular adaptation. Termination of the ISR is regulated by the constitutively expressed CReP and stress‐inducible phosphatase GADD34 that dephosphorylate eIF2α. For more details, see main text and Table 1. Arrows denote activation or induction, while blunt lines indicate inhibition.
Figure 2
Figure 2. Model for eIF2‐mediated translational control of ATF4
During the ISR, phosphorylation of eIF2α subunit of eIF2 complex inhibits eIF2B‐mediated exchange of eIF2‐GDP to eIF2‐GTP, thus reducing the formation of ternary complex consisting of eIF2‐GTP‐methionyl‐initiator tRNA. Under normal conditions, due to abundance of the ternary complex, ribosomes initiate scanning at upstream open reading frame uORF1 of ATF4 transcript and quickly re‐initiate at uORF2. uORF2 overlaps out‐of‐frame with ATF4 coding DNA sequence (CDS) preventing ATF4 translation. During cell stress, limiting ternary complex availability leads to longer ribosomal scanning along the ATF4 transcript enabling re‐initiation of translation at the ATF4 CDS.
Figure 3
Figure 3. Schematic ATF4 protein structure
ATF4 protein consists of 351 amino acids organized into several domains and motifs. It contains basic domain for DNA binding and leucine zipper domain involved in protein–protein interactions. ATF4 has an oxygen‐dependent degradation domain, which is recognized by PHD3. ATF4 has β‐TrCP recognition motif, which is a degradation motif. Depending on the phosphorylation events mainly at S219, ATF4 is recognized by β‐TrCP and targeted for proteasomal degradation.
Figure 4
Figure 4. Pharmacological approaches for targeting the components of ISR
Schematic representation of ISR signaling indicates the effect of eIF2α phosphorylation on translational control. eIF2α phosphorylation can be either stimulated through chemical activators of eIF2α kinases such as histidinol 220, asparaginase 217, halofuginone 253, arginine deiminase 219, BTdCPU 215, BEPP monohydrochloride 221, and CCT020312 216, or prevented using indirubin‐3′‐monoxime, SP600125, and SyK to inhibit GSK2 244, GSK2606414 and GSK2656157 to block PERK activation 240, 254, C16 and 2‐aminopurine to modulate PKR 242, 255, and aminopyrazolindane to inhibit HRI 243. Salubrinal 223 prolongs ISR through an unknown mechanism, while guanabenz 226 and Sephin1 224 block GADD34, and nelfinavir 231 decreases CReP expression and affects CReP–PP1 complex binding to eIF2α. The consequences of eIF2α phosphorylation can be reversed using ISRIB 245. See text for more details. Arrows point to enzyme activation, bar‐headed lines point to enzyme inhibition, dashed lines indicate the lack of known target, yellow boxes indicate the activators of ISR signaling, and pink boxes indicate the negative regulators of ISR signaling.
See this image and copyright information in PMC

References

    1. Ron D (2002) Translational control in the endoplasmic reticulum stress response. J Clin Invest 110: 1383–1388 - VSports手机版 - PMC - PubMed
    1. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R et al (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619–633 - PubMed
    1. Brostrom CO, Prostko CR, Kaufman RJ, Brostrom MA (1996) Inhibition of translational initiation by activators of the glucose‐regulated stress protein and heat shock protein stress response systems. Role of the interferon‐inducible double‐stranded RNA‐activated eukaryotic initiation factor 2alpha kinase. J Biol Chem 271: 24995–25002 - "V体育ios版" PubMed
    1. Dever TE, Feng L, Wek RC, Cigan AM, Donahue TF, Hinnebusch AG (1992) Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene‐specific translational control of GCN4 in yeast. Cell 68: 585–596 - PubMed
    1. Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34: 7–11 - PubMed