Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
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.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2002 Nov;110(10):1389-98.
doi: 10.1172/JCI16886.

Orchestrating the unfolded protein response in health and disease

Randal J Kaufman  1
Affiliations
Review

Orchestrating the unfolded protein response in health and disease

Randal J Kaufman. J Clin Invest. 2002 Nov.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Signaling the UPR in eukaryotes. Three proximal sensors, IRE1, PERK, and ATF6, coordinately regulate the UPR through their various signaling pathways. Whereas IRE1 and PERK are dispensable for many aspects of the response, ATF6 cleavage is required for UPR transcriptional induction and appears to be the most significant of these effectors in mammalian cells. BiP negatively regulates these pathways. BiP interacts with ATF6 to prevent its transport to the Golgi compartment (a). BiP binds to the lumenal domains of IRE1 (b) and PERK (c) to prevent their dimerization. As unfolded proteins accumulate, they bind BiP and reduce the amount of BiP available to bind and inhibit activation of IRE1, PERK, and ATF6. (a) BiP release from ATF6 permits transport to the Golgi compartment. In the Golgi, ATF6 is cleaved by S1P and S2P proteases to yield a cytosolic fragment that migrates to the nucleus to activate transcription of responsive genes, including XBP1. (b) BiP release from IRE1 permits dimerization to activate its kinase and RNase activities to initiate XBP1 mRNA splicing. XBP1 splicing removes a 26-base intron, creating a translational frameshift to yield a more potent transcriptional activator. (c) BiP release permits PERK dimerization and activation to phosphorylate Ser51 on eIF2α to reduce the frequency of AUG initiation codon recognition. As eIF2α phosphorylation reduces the functional level of eIF2, the general rate of translation initiation is reduced. However, selective mRNAs, such as ATF4 mRNA, are preferentially translated under these conditions, possibly by the presence of open reading frames within the 5′ untranslated region of the mRNA. Upon recovery from the UPR, GADD34 _targets PP1 to dephosphorylate eIF2α and increase protein translation.
Figure 2
Figure 2
Signaling UPR-mediated cell death. The activation of procaspase-12 is likely the major pathway that induces apoptosis in response to ER stress. Upon activation of the UPR, c-Jun-N-terminal inhibitory kinase (JIK) release from procaspase-12 permits clustering and activation of procaspase-12. Caspase-12 activates procaspase-9 to activate procaspase-3, the executioner of cell death. In addition, activated IRE1 binds JIK and recruits TRAF2, which signals through apoptosis-signaling kinase 1 (ASK1) and JNK to promote mitochondria-dependent apoptosis. In addition, in vitro studies suggest that localized calcium release from the ER activates m-calpain to cleave and activate procaspase-12. Upon UPR activation, procaspase-7 is activated and recruited to the ER membrane. Finally, IRE1, PERK, and ATF6 induce transcription of several genes encoding apoptotic functions, including CHOP/GADD153. CSP, caspase; pCSP, procaspase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Horwich A. Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J Clin Invest. 2002;110:1221–1232. doi:10.1172/JCI200216781. - PMC - PubMed
    1. Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110:1383–1388. doi:10.1172/JCI200216784. - PMC - PubMed
    1. Lee AS. Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol. 1992;4:267–273. - PubMed
    1. Kaufman RJ, et al. The unfolded protein response in nutrient sensing and differentiation. Nat Rev Mol Cell Biol. 2002;3:411–421. - PubMed
    1. Ellgaard L, Helenius A. ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol. 2001;13:431–437. - PubMed

Publication types

MeSH terms

  NODES
chat 1
twitter 2