Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response

doi:10.1101/CSHPERSPECT.A013169

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Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response

Journal Article•DOI•

Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response

Brooke M. Gardner¹, David Pincus¹, Katja Gotthardt¹, Ciara M Gallagher¹, Peter Walter¹ - Show less +1 more•Institutions (1)

University of California, San Francisco¹

01 Mar 2013-Cold Spring Harbor Perspectives in Biology (Cold Spring Harbor Lab)-Vol. 5, Iss: 3

TL;DR: The mechanistic principles of ER stress sensing are the focus of this review, and yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation.

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Abstract: Secretory and transmembrane proteins enter the endoplasmic reticulum (ER) as unfolded proteins and exit as either folded proteins in transit to their target organelles or as misfolded proteins targeted for degradation. The unfolded protein response (UPR) maintains the protein-folding homeostasis within the ER, ensuring that the protein-folding capacity of the ER meets the load of client proteins. Activation of the UPR depends on three ER stress sensor proteins, Ire1, PERK, and ATF6. Although the consequences of activation are well understood, how these sensors detect ER stress remains unclear. Recent evidence suggests that yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation. BiP dissociation from Ire1 regulates this oligomeric equilibrium, ultimately modulating Ire1’s sensitivity and duration of activation. The mechanistic principles of ER stress sensing are the focus of this review.

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Journal Article•DOI•

Endoplasmic Reticulum Stress and Associated ROS

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Hafiz Maher Ali Zeeshan¹, Geum Hwa Lee¹, Hyung-Ryong Kim², Han-Jung Chae¹•Institutions (2)

Chonbuk National University¹, Wonkwang University²

02 Mar 2016-International Journal of Molecular Sciences

TL;DR: Persistent ER stress and protein misfolding-initiated ROS cascades and their significant roles in the pathogenesis of multiple human disorders, including neurodegenerative diseases, diabetes mellitus, atherosclerosis, inflammation, ischemia, and kidney and liver diseases are reviewed.

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Abstract: The endoplasmic reticulum (ER) is a fascinating network of tubules through which secretory and transmembrane proteins enter unfolded and exit as either folded or misfolded proteins, after which they are directed either toward other organelles or to degradation, respectively. The ER redox environment dictates the fate of entering proteins, and the level of redox signaling mediators modulates the level of reactive oxygen species (ROS). Accumulating evidence suggests the interrelation of ER stress and ROS with redox signaling mediators such as protein disulfide isomerase (PDI)-endoplasmic reticulum oxidoreductin (ERO)-1, glutathione (GSH)/glutathione disuphide (GSSG), NADPH oxidase 4 (Nox4), NADPH-P450 reductase (NPR), and calcium. Here, we reviewed persistent ER stress and protein misfolding-initiated ROS cascades and their significant roles in the pathogenesis of multiple human disorders, including neurodegenerative diseases, diabetes mellitus, atherosclerosis, inflammation, ischemia, and kidney and liver diseases.

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579 citations

Journal Article•DOI•

IRE1: ER stress sensor and cell fate executor

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Yani Chen¹, Federica Brandizzi¹•Institutions (1)

Michigan State University¹

01 Nov 2013-Trends in Cell Biology

TL;DR: An updated scenario of the IRE1 signaling model is provided, a discussion of emerging IRE 1 sensing mechanisms is discussed, features among species are compared, and exciting future directions in UPR research are outlined.

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431 citations

Cites background from "Endoplasmic Reticulum Stress Sensin..."

...ER stress-sensing mechanisms are intensively studied in yeast and animals [77]....
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Journal Article•DOI•

Oxidative Stress and Neurodegenerative Disorders

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Jie Li, Wuliji O, Wei Li, Zhi-Gang Jiang¹, Hossein A. Ghanbari - Show less +1 more•Institutions (1)

Jilin University¹

16 Dec 2013-International Journal of Molecular Sciences

TL;DR: The source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS are summarized.

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Abstract: Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs.

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420 citations

Cites background from "Endoplasmic Reticulum Stress Sensin..."

...ATF6 promotes folding of protein and removal of misfolded protein by upregulation of chaperones, foldases, and components of the ERAD machinery, while IRE1 and PERK are functionally involved in both reducing ER protein load and triggering apoptosis [112]....
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Journal Article•DOI•

The role of MAPK signalling pathways in the response to endoplasmic reticulum stress

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Nicola J. Darling¹, Simon J. Cook¹•Institutions (1)

Babraham Institute¹

01 Oct 2014-Biochimica et Biophysica Acta

TL;DR: UPR signalling and the activation of MAPK signalling pathways in response to ER stress are reviewed and several diseases, including cancer, type II diabetes and retinal degeneration are described, where activation of the UPR andMAPK signalling contribute to disease progression and highlight potential avenues for therapeutic intervention.

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336 citations

Cites background from "Endoplasmic Reticulum Stress Sensin..."

...Similar to IRE1, active PERK forms higher order oligomers following ER stress [26], but there is currently no evidence that direct interaction with unfolded proteins is required for PERK activation [75]....
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Journal Article•DOI•

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

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Sara K. Young¹, Ronald C. Wek¹•Institutions (1)

Indiana University¹

12 Aug 2016-Journal of Biological Chemistry

TL;DR: This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.

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278 citations

Cites background from "Endoplasmic Reticulum Stress Sensin..."

...uORF translation can also result in activation of the mRNA decay pathways, thus adding another layer to the mechanisms in which uORFs can negatively regulate downstream translation (82)....
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References

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The PyMOL Molecular Graphics System

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W. L. Delano

01 Jan 2002

19,213 citations

Journal Article•DOI•

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

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Caroline E. Shamu¹, Peter Walter¹•Institutions (1)

University of California, San Francisco¹

17 Jun 1996-The EMBO Journal

TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.

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Abstract: The transmembrane kinase Ire1p is required for activation of the unfolded protein response (UPR), the increase in transcription of genes encoding endoplasmic reticulum (ER) resident proteins that occurs in response to the accumulation of unfolded proteins in the ER. Ire1p spans the ER membrane (or the nuclear membrane with which the ER is continuous), with its kinase domain localized in the cytoplasm or in the nucleus. Consistent with this arrangement, it has been proposed that Ire1p senses the accumulation of unfolded proteins in the ER and transmits the signal across the membrane toward the transcription machinery, possibly by phosphorylating downstream components of the UPR pathway. Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by other Ire1p molecules as a result of oligomerization. In addition to its kinase domain, a C-terminal tail domain of Ire1p is required for induction of the UPR. The role of the tail is probably to bind other proteins that transmit the unfolded protein signal to the nucleus.

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12,185 citations

"Endoplasmic Reticulum Stress Sensin..." refers background in this paper

...mutants impaired in nucleotide binding lose RNase activity, whereas mutants impaired in phosphotransfer, but retaining nucleotide binding, maintain RNase activity (Shamu and Walter 1996; Chawla et al. 2011; Rubio et al. 2011)....
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...…this article as Cold Spring Harb Perspect Biol 2013;5:a013169 3 mutants impaired in nucleotide binding lose RNase activity, whereas mutants impaired in phosphotransfer, but retaining nucleotide binding, maintain RNase activity (Shamu and Walter 1996; Chawla et al. 2011; Rubio et al. 2011)....
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Journal Article•DOI•

The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation

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Peter Walter¹, David Ron²•Institutions (2)

University of California, San Francisco¹, University of Cambridge²

25 Nov 2011-Science

TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.

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Abstract: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.

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4,468 citations

"Endoplasmic Reticulum Stress Sensin..." refers background in this paper

...Thus, the PERK branch first mediates a prosurvival response, which switches into a proapoptotic response on prolonged ER stress (Walter and Ron 2011)....
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...1) (Walter and Ron 2011)....
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Journal Article•DOI•

XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor

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Hiderou Yoshida¹, Toshie Matsui¹, Akira Yamamoto¹, Tetsuya Okada¹, Kazutoshi Mori¹ - Show less +1 more•Institutions (1)

Kyoto University¹

28 Dec 2001-Cell

TL;DR: The transcription factor XBP1, a target of ATF6, is identified as a mammalian substrate of such an unconventional mRNA splicing system and it is shown that only the spliced form of X BP1 can activate the UPR efficiently.

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3,635 citations

"Endoplasmic Reticulum Stress Sensin..." refers background in this paper

...Once activated, Ire1’s RNase specifically cleaves its mRNA substrate, HAC1 mRNA (homolog of ATF/CREB1) in yeast or XBP1 mRNA (X-box binding protein 1) (Cox and Walter 1996; Yoshida et al. 2001) in metazoan cells to initiate an unconventional splicing reaction....
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...regulates genes encoding ER quality control components (Sidrauski et al. 1996; Travers et al. 2000; Yoshida et al. 2001)....
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...…in metazoan cells, and the mature mRNA is translated to produce a potent bZIP transcription factor that up- 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a013169 regulates genes encoding ER quality control components (Sidrauski et al. 1996; Travers et al. 2000; Yoshida et al. 2001)....
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Journal Article•DOI•

Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

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Heather P. Harding¹, Yuhong Zhang¹, David Ron¹•Institutions (1)

New York University¹

21 Jan 1999-Nature

TL;DR: The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.

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Abstract: Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.

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3,058 citations

"Endoplasmic Reticulum Stress Sensin..." refers background in this paper

...…capacity through a broad transcriptional up-regulation of ER folding, lipid biosynthesis, and ERAD machinery (Travers et al. 2000) with a decrease in folding load through selective mRNA degradation and translational repression (Harding et al. 1999; Hollien and Weissman 2006; Hollien et al. 2009)....
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...Phosphorylation of eIF2a results in a reduction of general protein synthesis and thus a decrease in the load of proteins entering the ER (Harding et al. 1999)....
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