Translational control and the unfolded protein response

Ronald C. Wek, Douglas R. Cavener

Research output: Contribution to journalReview article

190 Citations (Scopus)

Abstract

Cellular stresses that disrupt the processing of proteins slated for the secretory pathway induce the unfolded protein response (UPR), a regulatory network involving both translational and transcriptional control mechanisms that is designed to expand the secretory pathway and alleviate cellular injury. PERK (PEK/EIF2AK3) mediates the translational control arm of the UPR by enhancing phosphorylation of eIF2. Phosphorylation of eIF2 reduces global protein synthesis, preventing further overload of the secretory pathway and allowing the cell to direct a new pattern of mRNA synthesis that enhances the processing capacity of the endoplasmic reticulum (ER). PERK also directs preferential translation of stress-related transcripts, including that encoding ATF4, a transcriptional activator that contributes to the UPR. Reduced global translation also leads to reduced levels of key regulatory proteins that are subject to rapid turnover, facilitating activation of transcription factors such as NF-B during cellular stress. This review highlights the mechanisms by which PERK monitors and is activated by accumulated misfolded protein in the ER, the processes by which PERK regulates both general and gene-specific translation that is central for the UPR, and the role of PERK in the process of cellular adaptation to ER stress and its impact in disease.

Original languageEnglish (US)
Pages (from-to)2357-2371
Number of pages15
JournalAntioxidants and Redox Signaling
Volume9
Issue number12
DOIs
StatePublished - Oct 1 2007

Fingerprint

Unfolded Protein Response
Secretory Pathway
Endoplasmic Reticulum
Proteins
Phosphorylation
Endoplasmic Reticulum Stress
Transcription Factors
Messenger RNA
Wounds and Injuries
Processing
Genes
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

@article{6e78ba400741457a82be0aab73b2340a,
title = "Translational control and the unfolded protein response",
abstract = "Cellular stresses that disrupt the processing of proteins slated for the secretory pathway induce the unfolded protein response (UPR), a regulatory network involving both translational and transcriptional control mechanisms that is designed to expand the secretory pathway and alleviate cellular injury. PERK (PEK/EIF2AK3) mediates the translational control arm of the UPR by enhancing phosphorylation of eIF2. Phosphorylation of eIF2 reduces global protein synthesis, preventing further overload of the secretory pathway and allowing the cell to direct a new pattern of mRNA synthesis that enhances the processing capacity of the endoplasmic reticulum (ER). PERK also directs preferential translation of stress-related transcripts, including that encoding ATF4, a transcriptional activator that contributes to the UPR. Reduced global translation also leads to reduced levels of key regulatory proteins that are subject to rapid turnover, facilitating activation of transcription factors such as NF-B during cellular stress. This review highlights the mechanisms by which PERK monitors and is activated by accumulated misfolded protein in the ER, the processes by which PERK regulates both general and gene-specific translation that is central for the UPR, and the role of PERK in the process of cellular adaptation to ER stress and its impact in disease.",
author = "Wek, {Ronald C.} and Cavener, {Douglas R.}",
year = "2007",
month = "10",
day = "1",
doi = "10.1089/ars.2007.1764",
language = "English (US)",
volume = "9",
pages = "2357--2371",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "12",

}

Translational control and the unfolded protein response. / Wek, Ronald C.; Cavener, Douglas R.

In: Antioxidants and Redox Signaling, Vol. 9, No. 12, 01.10.2007, p. 2357-2371.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Translational control and the unfolded protein response

AU - Wek, Ronald C.

AU - Cavener, Douglas R.

PY - 2007/10/1

Y1 - 2007/10/1

N2 - Cellular stresses that disrupt the processing of proteins slated for the secretory pathway induce the unfolded protein response (UPR), a regulatory network involving both translational and transcriptional control mechanisms that is designed to expand the secretory pathway and alleviate cellular injury. PERK (PEK/EIF2AK3) mediates the translational control arm of the UPR by enhancing phosphorylation of eIF2. Phosphorylation of eIF2 reduces global protein synthesis, preventing further overload of the secretory pathway and allowing the cell to direct a new pattern of mRNA synthesis that enhances the processing capacity of the endoplasmic reticulum (ER). PERK also directs preferential translation of stress-related transcripts, including that encoding ATF4, a transcriptional activator that contributes to the UPR. Reduced global translation also leads to reduced levels of key regulatory proteins that are subject to rapid turnover, facilitating activation of transcription factors such as NF-B during cellular stress. This review highlights the mechanisms by which PERK monitors and is activated by accumulated misfolded protein in the ER, the processes by which PERK regulates both general and gene-specific translation that is central for the UPR, and the role of PERK in the process of cellular adaptation to ER stress and its impact in disease.

AB - Cellular stresses that disrupt the processing of proteins slated for the secretory pathway induce the unfolded protein response (UPR), a regulatory network involving both translational and transcriptional control mechanisms that is designed to expand the secretory pathway and alleviate cellular injury. PERK (PEK/EIF2AK3) mediates the translational control arm of the UPR by enhancing phosphorylation of eIF2. Phosphorylation of eIF2 reduces global protein synthesis, preventing further overload of the secretory pathway and allowing the cell to direct a new pattern of mRNA synthesis that enhances the processing capacity of the endoplasmic reticulum (ER). PERK also directs preferential translation of stress-related transcripts, including that encoding ATF4, a transcriptional activator that contributes to the UPR. Reduced global translation also leads to reduced levels of key regulatory proteins that are subject to rapid turnover, facilitating activation of transcription factors such as NF-B during cellular stress. This review highlights the mechanisms by which PERK monitors and is activated by accumulated misfolded protein in the ER, the processes by which PERK regulates both general and gene-specific translation that is central for the UPR, and the role of PERK in the process of cellular adaptation to ER stress and its impact in disease.

UR - http://www.scopus.com/inward/record.url?scp=35848935017&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35848935017&partnerID=8YFLogxK

U2 - 10.1089/ars.2007.1764

DO - 10.1089/ars.2007.1764

M3 - Review article

C2 - 17760508

AN - SCOPUS:35848935017

VL - 9

SP - 2357

EP - 2371

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 12

ER -