Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.

Cellular Reprogramming Techniques Drug Discovery / methods Endoplasmic Reticulum / drug effects Endoribonucleases / genetics Gene Expression Regulation / drug effects HEK293 Cells Humans Protein Serine-Threonine Kinases / genetics Protein Unfolding Proteostasis / drug effects Unfolded Protein Response / drug effects X-Box Binding Protein 1 / genetics

Journal

Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976

Informations de publication

Date de publication:
10 2020
Historique:
received: 23 07 2019
accepted: 05 06 2020
pubmed: 22 7 2020
medline: 15 12 2020
entrez: 22 7 2020
Statut: ppublish

Résumé

Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.

Identifiants

DOI: 10.1038/s41589-020-0584-z PMID: 32690944 PMC: PMC7502540
pubmed: 32690944
doi: 10.1038/s41589-020-0584-z
pii: 10.1038/s41589-020-0584-z
pmc: PMC7502540
mid: NIHMS1601243
doi:

Substances chimiques

X-Box Binding Protein 1 0
XBP1 protein, human 0
ERN1 protein, human EC 2.7.11.1
Protein Serine-Threonine Kinases EC 2.7.11.1
Endoribonucleases EC 3.1.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1052-1061

Subventions

Organisme : NIA NIH HHS
ID : R01 AG046495
Pays : United States
Organisme : NIH HHS
ID : S10 OD025279
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095892
Pays : United States
Organisme : NIH HHS
ID : S10 OD026857
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS092829
Pays : United States
Organisme : NIA NIH HHS
ID : F31 AG063489
Pays : United States

Commentaires et corrections

Type : CommentIn

Références

Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
pubmed: 22116877 doi: 10.1126/science.1209038
Bernales, S., Papa, F. R. & Walter, P. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508 (2006).
pubmed: 16822172 doi: 10.1146/annurev.cellbio.21.122303.120200
Schroder, M. & Kaufman, R. J. ER stress and the unfolded protein response. Mutat Res. 569, 29–63 (2005).
pubmed: 15603751 doi: 10.1016/j.mrfmmm.2004.06.056
Patil, C. & Walter, P. Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr. Opin. Cell Biol. 13, 349–355 (2001).
pubmed: 11343907 doi: 10.1016/S0955-0674(00)00219-2
Shoulders, M. D. et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 3, 1279–1292 (2013).
pubmed: 23583182 pmcid: 3754422 doi: 10.1016/j.celrep.2013.03.024
Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).
pubmed: 14559994 pmcid: 207643
Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).
pubmed: 23624402 pmcid: 3692270 doi: 10.1038/ncb2738
Chang, T. K. et al. Coordination between two branches of the unfolded protein response determines apoptotic cell fate. Mol. Cell 71, 629–636 e5 (2018).
pubmed: 30118681 doi: 10.1016/j.molcel.2018.06.038
Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
pubmed: 18276881 doi: 10.1126/science.1141448
Chen, J. J., Genereux, J. C. & Wiseman, R. L. Endoplasmic reticulum quality control and systemic amyloid disease: impacting protein stability from the inside out. IUBMB Life 67, 404–413 (2015).
pubmed: 26018985 pmcid: 4485578 doi: 10.1002/iub.1386
Wong, M. Y. & Shoulders, M. D. Targeting defective proteostasis in the collagenopathies. Curr. Opin. Chem. Biol. 50, 80–88 (2019).
pubmed: 31028939 pmcid: 6588406 doi: 10.1016/j.cbpa.2019.02.021
Zhang, L., Zhang, C. & Wang, A. Divergence and conservation of the major UPR branch IRE1-bZIP signaling pathway across eukaryotes. Sci. Rep. 6, 27362 (2016).
pubmed: 27256815 pmcid: 4891664 doi: 10.1038/srep27362
Joshi, A. et al. Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. Oncotarget 6, 13019–13035 (2015).
pubmed: 25968568 pmcid: 4536996 doi: 10.18632/oncotarget.3864
Korennykh, A. V. et al. The unfolded protein response signals through high-order assembly of Ire1. Nature 457, 687–693 (2009).
pubmed: 19079236 doi: 10.1038/nature07661
Wang, L. et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat. Chem. Biol. 8, 982–989 (2012).
pubmed: 23086298 pmcid: 3508346 doi: 10.1038/nchembio.1094
Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001).
pubmed: 11779464 doi: 10.1016/S0092-8674(01)00611-0
Hollien, J. et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323–331 (2009).
pubmed: 19651891 pmcid: 2728407 doi: 10.1083/jcb.200903014
Tam, A. B., Koong, A. C. & Niwa, M. Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD. Cell Rep. 9, 850–858 (2014).
pubmed: 25437541 pmcid: 4486022 doi: 10.1016/j.celrep.2014.09.016
Bae, D., Moore, K. A., Mella, J. M., Hayashi, S. Y. & Hollien, J. Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress. J. Cell Biol. 218, 1118–1127 (2019).
pubmed: 30787040 pmcid: 6446841 doi: 10.1083/jcb.201809027
Valdes, P. et al. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc. Natl Acad. Sci. USA 111, 6804–6809 (2014).
pubmed: 24753614 doi: 10.1073/pnas.1321845111 pmcid: 4020088
Zuleta, A., Vidal, R. L., Armentano, D., Parsons, G. & Hetz, C. AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington’s disease. Biochem. Biophys. Res. Commun. 420, 558–563 (2012).
pubmed: 22445760 doi: 10.1016/j.bbrc.2012.03.033
Valenzuela, V. et al. Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis. 3, e272 (2012).
pubmed: 22337234 doi: 10.1038/cddis.2012.8
Cui, H., Deng, M., Zhang, Y., Yin, F. & Liu, J. Geniposide increases unfolded protein response-mediating HRD1 expression to accelerate APP degradation in primary cortical neurons. Neurochem. Res. 43, 669–680 (2018).
pubmed: 29427280 doi: 10.1007/s11064-018-2469-z
Kaneko, M. et al. Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J. Neurosci. 30, 3924–3932 (2010).
pubmed: 20237263 pmcid: 6632277 doi: 10.1523/JNEUROSCI.2422-09.2010
Chiang, W. C., Messah, C. & Lin, J. H. IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol. Biol. Cell 23, 758–770 (2012).
pubmed: 22219383 pmcid: 3290636 doi: 10.1091/mbc.e11-08-0663
Sifers, R. N. Intracellular processing of alpha1-antitrypsin. Proc. Am. Thorac. Soc. 7, 376–380 (2010).
pubmed: 21030516 pmcid: 3136957 doi: 10.1513/pats.201001-011AW
Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).
pubmed: 15486293 doi: 10.1126/science.1103160
Bi, X. et al. Endoplasmic reticulum chaperone GRP78 protects heart from ischemia/reperfusion injury through akt activation. Circ. Res. 122, 1545–1554 (2018).
pubmed: 29669712 pmcid: 5970094 doi: 10.1161/CIRCRESAHA.117.312641
Mendez, A. S. et al. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. eLife 4, e05434 (2015).
pmcid: 4436593 doi: 10.7554/eLife.05434
Ghosh, R. et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158, 534–548 (2014).
pubmed: 25018104 pmcid: 4244221 doi: 10.1016/j.cell.2014.07.002
Plate, L. et al. Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. eLife 5, e15550 (2016).
pubmed: 27435961 pmcid: 4954754 doi: 10.7554/eLife.15550
Iwawaki, T., Akai, R., Kohno, K. & Miura, M. A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat. Med. 10, 98–102 (2004).
pubmed: 14702639 doi: 10.1038/nm970
Cross, B. C. et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl Acad. Sci. USA 109, E869–E878 (2012).
pubmed: 22315414 doi: 10.1073/pnas.1115623109 pmcid: 3326519
Calamini, B. et al. Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8, 185–196 (2011).
pubmed: 22198733 pmcid: 3262058 doi: 10.1038/nchembio.763
Merour, J. Y., Buron, F., Ple, K., Bonnet, P. & Routier, S. The azaindole framework in the design of kinase inhibitors. Molecules 19, 19935–19979 (2014).
pubmed: 25460315 pmcid: 6271083 doi: 10.3390/molecules191219935
Grandjean, J. M. D. et al. Deconvoluting stress-responsive proteostasis signaling pathways for pharmacologic activation using targeted RNA sequencing. ACS Chem. Biol. 14, 784–795 (2019).
pubmed: 30821953 pmcid: 6474822 doi: 10.1021/acschembio.9b00134
Moore, K. & Hollien, J. Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status. Mol. Biol. Cell 26, 2873–2884 (2015).
pubmed: 26108623 pmcid: 4571326 doi: 10.1091/mbc.E15-02-0074
So, J. S. et al. Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 16, 487–499 (2012).
pubmed: 23040070 pmcid: 3475419 doi: 10.1016/j.cmet.2012.09.004
Wong, M. Y. et al. XBP1s activation can globally remodel N-glycan structure distribution patterns. Proc. Natl Acad. Sci. USA 115, E10089–E10098 (2018).
pubmed: 30305426 doi: 10.1073/pnas.1805425115 pmcid: 6205500
Urano, F. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664–666 (2000).
pubmed: 10650002 doi: 10.1126/science.287.5453.664
Chow, V. W., Mattson, M. P., Wong, P. C. & Gleichmann, M. An overview of APP processing enzymes and products. Neuromolecular Med. 12, 1–12 (2010).
pubmed: 20232515 pmcid: 2889200 doi: 10.1007/s12017-009-8104-z
Portelius, E. et al. Mass spectrometric characterization of amyloid-β species in the 7PA2 cell model of Alzheimer’s disease. J. Alzheimers Dis. 33, 85–93 (2013).
pubmed: 22886024 doi: 10.3233/JAD-2012-120994
Pera, M. et al. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 36, 3356–3371 (2017).
pubmed: 29018038 pmcid: 5731665 doi: 10.15252/embj.201796797
Krako, N. et al. Characterization of mitochondrial dysfunction in the 7PA2 cell model of Alzheimer’s disease. J. Alzheimers Dis. 37, 747–758 (2013).
pubmed: 23948918 doi: 10.3233/JAD-130728
Rainbolt, T. K., Lebeau, J., Puchades, C. & Wiseman, R. L. Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress. Cell Rep 14, 2041–2049 (2016).
pubmed: 26923599 pmcid: 4785047 doi: 10.1016/j.celrep.2016.02.011
Blackwood, E. A. et al. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat. Commun. 10, 187 (2019).
pubmed: 30643122 pmcid: 6331617 doi: 10.1038/s41467-018-08129-2
Kroeger, H. et al. The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Sci. Signal 11, eaan5785 (2018).
pubmed: 29440509 pmcid: 5957084 doi: 10.1126/scisignal.aan5785
Casas-Tinto, S. et al. The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum. Mol. Genet. 20, 2144–2160 (2011).
pubmed: 21389082 pmcid: 3090193 doi: 10.1093/hmg/ddr100
Tufanli, O. et al. Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc. Natl Acad. Sci. USA 114, E1395–E1404 (2017).
pubmed: 28137856 doi: 10.1073/pnas.1621188114 pmcid: 5338400
Rosen, D. A. et al. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci. Transl. Med. 11, eaau5266 (2019).
pubmed: 30728287 pmcid: 6936250 doi: 10.1126/scitranslmed.aau5266

Auteurs

Julia M D Grandjean (JMD)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Aparajita Madhavan (A)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Lauren Cech (L)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Bryan O Seguinot (BO)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Ryan J Paxman (RJ)

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Emery Smith (E)

Scripps Research Molecular Screening Center, The Scripps Research Institute, Jupiter, FL, USA.

Louis Scampavia (L)

Scripps Research Molecular Screening Center, The Scripps Research Institute, Jupiter, FL, USA.

Evan T Powers (ET)

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Christina B Cooley (CB)

Department of Chemistry, Trinity University, San Antonio, TX, USA.
ORCID: 0000-0001-9699-7682

Lars Plate (L)

Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA.

Timothy P Spicer (TP)

Scripps Research Molecular Screening Center, The Scripps Research Institute, Jupiter, FL, USA.

Jeffery W Kelly (JW)

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.

R Luke Wiseman (RL)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. wiseman@scripps.edu.
ORCID: 0000-0001-9287-6840

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Techniques de reprogrammation cellulaire › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Réticulum endoplasmique › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Ribonucléases › Endoribonucleases › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Pliage des protéines › Dépliement des protéines › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Métabolisme › Homéostasie protéique › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Réponse aux protéines mal repliées › Pharmacologic IRE1/XBP1s activation confers...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Protéine-1 liant la boite X › Pharmacologic IRE1/XBP1s activation confers...