Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1

Frontiers in Molecular Biosciences, Год журнала: 2019, Номер 6

Опубликована: Март 12, 2019

The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. cellular requirement to synthesize proteins within the ER matched by its capacity. However, physiological demands or aberrations may result imbalance which can lead accumulation of misfolded protein, also known as "ER stress." unfolded response (UPR) a cell-signaling system that readjusts capacity restore homeostasis. key UPR signal activator, IRE1, responds stress propagating from cytosol. Here, we discuss structural molecular basis IRE1 signaling, with particular focus on novel mechanistic advances. We draw comparison between recently proposed allosteric model induction role Hsp70 during polypeptide import mitochondrial matrix.

Язык: Английский

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UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

Nature Structural & Molecular Biology, Год журнала: 2019, Номер 26(11), С. 1053 - 1062

Опубликована: Ноя. 1, 2019

Язык: Английский

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Reshaping endoplasmic reticulum quality control through the unfolded protein response

Molecular Cell, Год журнала: 2022, Номер 82(8), С. 1477 - 1491

Опубликована: Апрель 1, 2022

Язык: Английский

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Endoplasmic reticulum stress-mediated cell death in liver injury

Cell Death and Disease, Год журнала: 2022, Номер 13(12)

Опубликована: Дек. 19, 2022

The endoplasmic reticulum is an important intracellular organelle that plays role in maintaining cellular homeostasis. Endoplasmic stress (ERS) and unfolded protein response (UPR) are induced when the body exposed to adverse external stimuli. It has been established ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, pyroptosis, through three major transmembrane receptors on ER membrane, inositol requirement enzyme 1α, kinase-like kinase activating transcription factor 6. These modes of play occurrence development various diseases, such as neurodegenerative inflammation, metabolic liver injury. As largest organ, rich enzymes, carries out functions metabolism secretion, body's main site synthesis. Accordingly, a well-developed system present hepatocytes help perform its physiological functions. Current evidence suggests closely related stages injury, caused by may be key In addition, increasing modulating great potential for treating This article provided comprehensive overview relationship between four types death. Moreover, we discussed mechanism UPR injuries their therapeutic strategies.

Язык: Английский

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ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum

Physiological Reviews, Год журнала: 2022, Номер 102(3), С. 1393 - 1448

Опубликована: Фев. 21, 2022

ER-phagy (reticulophagy) defines the degradation of portions endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part self-digestion (i.e., autophagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance ER subdomains participates control size activity during stress, reestablishment homeostasis after stress resolution, removal parts aberrant potentially cytotoxic has been segregated. relies on individual and/or concerted activation receptors, peripheral integral membrane proteins that share presence LC3/Atg8-binding motifs their cytosolic domains. involves physical separation from bulk network delivery to endolysosomal/vacuolar catabolic district. This last step accomplished by a variety mechanisms including macro-ER-phagy (in fragments are sequestered double-membrane autophagosomes eventually fuse lysosomes/vacuoles), micro-ER-phagy directly engulfed endosomes/lysosomes/vacuoles), direct fusion ER-derived vesicles lysosomes/vacuoles. dysfunctional specific human diseases, its regulators subverted pathogens, highlighting crucial role for cell organism life.

Язык: Английский

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The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Biomedicines, Год журнала: 2021, Номер 9(2), С. 156 - 156

Опубликована: Фев. 5, 2021

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches the Unfolded Protein Response (UPR) signaling pathway, which activated upon endoplasmic reticulum (ER) stress conditions. It known to be capable inducing both pro-survival and pro-apoptotic cellular responses, are strictly related numerous human pathologies. Among others, IRE1 activity has been confirmed increased in cancer, neurodegeneration, inflammatory metabolic disorders, associated with an accumulation misfolded proteins within ER lumen resulting Emerging evidence suggests that genetic or pharmacological modulation may have significant impact on cell viability, thus promising step forward towards development novel therapeutic strategies. In this review, we extensively describe structural analysis molecule, molecular dynamics activation, interconnection between it other UPR regard its potential use target. Detailed knowledge characteristics protein activation allow design specific RNase modulators act drug candidates.

Язык: Английский

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Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Март 20, 2024

Abstract The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads stress (ER stress). As ER ensues, protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, kinase R-like kinase, activating transcription factor 6 promptly activates enhance ER’s protein-folding capacity restore homeostasis. However, prolonged levels propels UPR towards cellular demise subsequent inflammatory cascade, contributing development human diseases, including cancer, neurodegenerative disorders, diabetes. Notably, increased expression all pathways has been observed in these pathologies, reduction molecule correlates with decreased proliferation disease-associated target cells. Consequently, therapeutic strategies targeting stress-related interventions have attracted significant research interest. In this review, we elucidate critical role metabolic, offering novel approaches for conditions.

Язык: Английский

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ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Ноя. 7, 2019

The endoplasmic reticulum (ER) produces about 40% of the nucleated cell's proteome. ER size and content in molecular chaperones increase upon physiologic pathologic stresses on activation unfolded protein responses (UPR). On stress resolution, mammalian is remodeled to pre-stress, function LC3-binding activity translocon component SEC62. This elicits recov-ER-phagy, i.e., delivery excess generated during phase endolysosomes (EL) for clearance. Here, ultrastructural genetic analyses reveal that recov-ER-phagy entails LC3 lipidation machinery proceeds via piecemeal micro-ER-phagy, where RAB7/LAMP1-positive EL directly engulf processes rely Endosomal Sorting Complex Required Transport (ESCRT)-III CHMP4B accessory AAA+ ATPase VPS4A. Thus, ESCRT-III-driven micro-ER-phagy emerges as a key catabolic pathway activated remodel recovery from stress.

Язык: Английский

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Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

Cold Spring Harbor Perspectives in Biology, Год журнала: 2019, Номер 11(8), С. a033928 - a033928

Опубликована: Янв. 22, 2019

Patrick G. Needham, Christopher J. Guerriero and Jeffrey L. Brodsky Department of Biological Sciences, University Pittsburgh, Pennsylvania 15260 Correspondence: jbrodsky{at}pitt.edu

Язык: Английский

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Small molecule strategies to harness the unfolded protein response: where do we go from here?

Journal of Biological Chemistry, Год журнала: 2020, Номер 295(46), С. 15692 - 15711

Опубликована: Сен. 4, 2020

The unfolded protein response (UPR) plays a central role in regulating endoplasmic reticulum (ER) and global cellular physiology to pathologic ER stress. UPR is comprised of three signaling pathways activated downstream the membrane proteins IRE1, ATF6, PERK. Once activated, these initiate transcriptional translational that functions alleviate stress, adapt physiology, dictate cell fate. Imbalances are implicated pathogenesis numerous, etiologically-diverse diseases, including many neurodegenerative misfolding diabetes, ischemic disorders, cancer. This has led significant interest establishing pharmacologic strategies selectively modulate or PERK both ameliorate imbalances different diseases define importance diverse organismal contexts. Recently, there been progress identification characterization modulating compounds, providing new opportunities probe potentially therapeutic implications human disease. 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Pharmacological intervention.Nat. 15 (31320759): 764-77510.1038/s41589-019-0326-2Crossref (70) activate inhibit select provide individual pathways, how they were discovered, described action, applicability studying models. addition, summarize UPR-modulating confer increased guide future next-generation compounds. highly conserved arm UPR, found organisms yeast humans (20Hollien 32Nikawa Yamashita putative containing membrane-spanning domain required inositol phototrophy Saccharomyces cerevisiae.Mol. Microbiol. 1992; (1625574): 1441-144610.1111/j.1365-2958.1992.tb00864.xCrossref Notably, was first identified likely well-studied. I comprising domains: luminal domain, cytosolic RNase 2, A B) (33Tirasophon W. Welihinda A.A. nucleus requires novel bifunctional kinase/endoribonuclease (Ire1p) mammalian cells.Genes 1998; (9637683): 1812-182410.1101/gad.12.12.1812Crossref 34Cox J.S. Shamu C.E. 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Structure Ire1 complex response.EMBO 30 (21317875): 894-90510.1038/emboj.2011.18Crossref (145) Extensive structural biochemical studies characterized displacement loop upon ATP binding, due direct bound ADP DFG motif active site cause coordinated changes allosterically cleaves mRNA X-box (XBP1), then re-ligated RTCB RNA ligase, resulting frameshift transcript (49Sidrauski site-specific endonuclease initiates splicing 1997; 90 (9323131): 1031-103910.1016/S0092-8674(00)80369-4Abstract (601) 50Yoshida Matsui Yamamoto Okada Mori XBP1 induced spliced produce factor.Cell. (11779464): 881-89110.1016/S0092-8674(01)00611-0Abstract (2617) 51Jurkin Henkel Nielsen A.F. Minnich Popow Kaufmann Heindl Hoffmann Busslinger Martinez tRNA ligase mediates controls antibody secretion plasma cells.EMBO 2014; 33 (25378478): 2922-293610.15252/embj.201490332Crossref (79) 52Lu Liang F.X. synthetic identifies RtcB.Mol. 55 (25087875): 758-77010.1016/j.molcel.2014.06.032Abstract (110) 53Kosmaczewski S.G. Edwards T.J. Han Eckwahl Meyer B.I. Peach Hesselberth Wolin Hammarlund RtcB lig

Язык: Английский

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