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ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.

Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D
Mol Cell 81 88-103.e6 (2021)
Related entries: 7d44, 7d45, 7d46

Cited: 53 times
EuropePMC logo PMID: 33220178

Abstract

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

Articles - 7d43 mentioned but not cited (2)

  1. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D. Mol Cell 81 88-103.e6 (2021)
  2. Higher-order phosphatase-substrate contacts terminate the integrated stress response. Yan Y, Harding HP, Ron D. Nat Struct Mol Biol 28 835-846 (2021)


Reviews citing this publication (8)

  1. Pharmacological targeting of endoplasmic reticulum stress in disease. Marciniak SJ, Chambers JE, Ron D. Nat Rev Drug Discov 21 115-140 (2022)
  2. PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate? Shacham T, Patel C, Lederkremer GZ. Biomolecules 11 354 (2021)
  3. Principles and functions of condensate modifying drugs. Patel A, Mitrea D, Namasivayam V, Murcko MA, Wagner M, Klein IA. Front Mol Biosci 9 1007744 (2022)
  4. Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response. Wek RC, Anthony TG, Staschke KA. Antioxid Redox Signal 39 351-373 (2023)
  5. The integrated stress response in cancer progression: a force for plasticity and resistance. Lines CL, McGrath MJ, Dorwart T, Conn CS. Front Oncol 13 1206561 (2023)
  6. Regulation and function of elF2B in neurological and metabolic disorders. Hanson FM, Hodgson RE, de Oliveira MIR, Allen KE, Campbell SG. Biosci Rep 42 BSR20211699 (2022)
  7. Move and countermove: the integrated stress response in picorna- and coronavirus-infected cells. Aloise C, Schipper JG, de Groot RJ, van Kuppeveld FJ. Curr Opin Immunol 79 102254 (2022)
  8. Protection of eIF2B from inhibitory phosphorylated eIF2: A viral strategy to maintain mRNA translation during the PKR-triggered integrated stress response. Ito T, Wuerth JD, Weber F. J Biol Chem 299 105287 (2023)

Articles citing this publication (43)

  1. eIF2B conformation and assembly state regulate the integrated stress response. Schoof M, Boone M, Wang L, Lawrence R, Frost A, Walter P. Elife 10 e65703 (2021)
  2. A structural biology community assessment of AlphaFold2 applications. Akdel M, Pires DEV, Pardo EP, Jänes J, Zalevsky AO, Mészáros B, Bryant P, Good LL, Laskowski RA, Pozzati G, Shenoy A, Zhu W, Kundrotas P, Serra VR, Rodrigues CHM, Dunham AS, Burke D, Borkakoti N, Velankar S, Frost A, Basquin J, Lindorff-Larsen K, Bateman A, Kajava AV, Valencia A, Ovchinnikov S, Durairaj J, Ascher DB, Thornton JM, Davey NE, Stein A, Elofsson A, Croll TI, Beltrao P. Nat Struct Mol Biol 29 1056-1067 (2022)
  3. Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice. Helseth AR, Hernandez-Martinez R, Hall VL, Oliver ML, Turner BD, Caffall ZF, Rittiner JE, Shipman MK, King CS, Gradinaru V, Gerfen C, Costa-Mattioli M, Calakos N. Science 372 eabe1931 (2021)
  4. Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. Echavarría-Consuegra L, Cook GM, Busnadiego I, Lefèvre C, Keep S, Brown K, Doyle N, Dowgier G, Franaszek K, Moore NA, Siddell SG, Bickerton E, Hale BG, Firth AE, Brierley I, Irigoyen N. PLoS Pathog 17 e1009644 (2021)
  5. Epithelial Endoplasmic Reticulum Stress Enhances the Risk of Muc5b-associated Lung Fibrosis. Dobrinskikh E, Hennessy CE, Kurche JS, Kim E, Estrella AM, Cardwell J, Yang IV, Schwartz DA. Am J Respir Cell Mol Biol 68 62-74 (2023)
  6. Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis. Watanabe S, Markov NS, Lu Z, Piseaux Aillon R, Soberanes S, Runyan CE, Ren Z, Grant RA, Maciel M, Abdala-Valencia H, Politanska Y, Nam K, Sichizya L, Kihshen HG, Joshi N, McQuattie-Pimentel AC, Gruner KA, Jain M, Sznajder JI, Morimoto RI, Reyfman PA, Gottardi CJ, Budinger GRS, Misharin AV. Proc Natl Acad Sci U S A 118 e2101100118 (2021)
  7. APOE4 confers transcriptomic and functional alterations to primary mouse microglia. Machlovi SI, Neuner SM, Hemmer BM, Khan R, Liu Y, Huang M, Zhu JD, Castellano JM, Cai D, Marcora E, Goate AM. Neurobiol Dis 164 105615 (2022)
  8. Endoplasmic reticulum oxidoreductin 1-alpha deficiency and activation of protein translation synergistically impair breast tumour resilience. Varone E, Decio A, Barbera MC, Bolis M, Di Rito L, Pisati F, Giavazzi R, Zito E. Br J Pharmacol 179 5180-5195 (2022)
  9. Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages. Tong F, Hu H, Xu Y, Zhou Y, Xie R, Lei T, Du Y, Yang W, He S, Huang Y, Gong T, Gao H. Acta Pharm Sin B 13 3471-3488 (2023)
  10. Ribosome changes reprogram translation for chemosurvival in G0 leukemic cells. Datta C, Truesdell SS, Wu KQ, Bukhari SIA, Ngue H, Buchanan B, Le Tonqueze O, Lee S, Kollu S, Granovetter MA, Boukhali M, Kreuzer J, Batool MS, Balaj L, Haas W, Vasudevan S. Sci Adv 8 eabo1304 (2022)
  11. Sugar phosphate activation of the stress sensor eIF2B. Hao Q, Heo JM, Nocek BP, Hicks KG, Stoll VS, Remarcik C, Hackett S, LeBon L, Jain R, Eaton D, Rutter J, Wong YL, Sidrauski C. Nat Commun 12 3440 (2021)
  12. A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation. Boone M, Wang L, Lawrence RE, Frost A, Walter P, Schoof M. Elife 11 e76171 (2022)
  13. Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response. Yousuf MS, Sahn JJ, Yang H, David ET, Shiers S, Mancilla Moreno M, Iketem J, Royer DM, Garcia CD, Zhang J, Hong VM, Mian SM, Ahmad A, Kolber BJ, Liebl DJ, Martin SF, Price TJ. Proc Natl Acad Sci U S A 120 e2306090120 (2023)
  14. Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer's disease. Hu Z, Yu P, Zhang Y, Yang Y, Zhu M, Qin S, Xu JT, Duan D, Wu Y, Wang D, Rowan MJ, Hu NW. Transl Psychiatry 12 96 (2022)
  15. Lung Injury Induces Alveolar Type 2 Cell Hypertrophy and Polyploidy with Implications for Repair and Regeneration. Weng A, Maciel Herrerias M, Watanabe S, Welch LC, Flozak AS, Grant RA, Aillon RP, Dada LA, Han SH, Hinchcliff M, Misharin AV, Budinger GRS, Gottardi CJ. Am J Respir Cell Mol Biol 66 564-576 (2022)
  16. Synonymous codon usage regulates translation initiation. Barrington CL, Galindo G, Koch AL, Horton ER, Morrison EJ, Tisa S, Stasevich TJ, Rissland OS. Cell Rep 42 113413 (2023)
  17. The GCN2/eIF2αK stress kinase regulates PP1 to ensure mitotic fidelity. Stonyte V, Mastrangelopoulou M, Timmer R, Lindbergsengen L, Vietri M, Campsteijn C, Grallert B. EMBO Rep 24 e56100 (2023)
  18. The stressosome, a caspase-8-activating signalling complex assembled in response to cell stress in an ATG5-mediated manner. Mnich K, Koryga I, Pakos-Zebrucka K, Thomas M, Logue SE, Eriksson LA, Gorman AM, Samali A. J Cell Mol Med 25 8809-8820 (2021)
  19. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. Liu K, Zhao C, Adajar RC, DeZwaan-McCabe D, Thomas Rutkowski D. EMBO Rep 25 228-253 (2024)
  20. A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling. Lawrence RE, Shoemaker SR, Deal A, Sangwan S, Anand AA, Wang L, Marqusee S, Walter P. Nat Chem Biol (2023)
  21. Acute liver steatosis translationally controls the epigenetic regulator MIER1 to promote liver regeneration in a study with male mice. Chen Y, Chen L, Wu X, Zhao Y, Wang Y, Jiang D, Liu X, Zhou T, Li S, Wei Y, Liu Y, Hu C, Zhou B, Qin J, Ying H, Ding Q. Nat Commun 14 1521 (2023)
  22. Adipose stem cell-derived extracellular vesicles ameliorates corticosterone-induced apoptosis in the cortical neurons via inhibition of ER stress. Hyun SA, Lee YJ, Jang S, Ko MY, Lee CY, Cho YW, Yun YE, Lee BS, Seo JW, Moon KS, Ka M. Stem Cell Res Ther 13 110 (2022)
  23. Adjunctive Integrated Stress Response Inhibition Accelerates Tuberculosis Clearance in Mice. Krug S, Prasad P, Xiao S, Lun S, Ruiz-Bedoya CA, Klunk M, Ordonez AA, Jain SK, Srikrishna G, Kramnik I, Bishai WR. mBio 14 e0349622 (2023)
  24. Systematic Review ER stress as a trigger of UPR and ER-phagy in cancer growth and spread. Cherubini A, Zito E. Front Oncol 12 997235 (2022)
  25. Flurochloridone Induced Cell Apoptosis via ER Stress and eIF2α-ATF4/ATF6-CHOP-Bim/Bax Signaling Pathways in Mouse TM4 Sertoli Cells. Zhang F, Ni Z, Zhao S, Wang Y, Chang X, Zhou Z. Int J Environ Res Public Health 19 4564 (2022)
  26. GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity. Kershaw CJ, Jennings MD, Cortopassi F, Guaita M, Al-Ghafli H, Pavitt GD. iScience 24 103454 (2021)
  27. Inhibition of Nonsense-Mediated Decay Induces Nociceptive Sensitization through Activation of the Integrated Stress Response. de la Peña JB, Chase R, Kunder N, Smith PR, Lou TF, Stanowick A, Suresh P, Shukla T, Butcher SE, Price TJ, Campbell ZT. J Neurosci 43 2921-2933 (2023)
  28. Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma. Borankova K, Krchniakova M, Leck LYW, Kubistova A, Neradil J, Jansson PJ, Hogarty MD, Skoda J. Cell Death Dis 14 747 (2023)
  29. Neuron-specific translational control shift ensures proteostatic resilience during ER stress. Wolzak K, Nölle A, Farina M, Abbink TE, van der Knaap MS, Verhage M, Scheper W. EMBO J 41 e110501 (2022)
  30. Nutrient-dependent regulation of β-cell proinsulin content. Xu X, Arunagiri A, Alam M, Haataja L, Evans CR, Zhao I, Castro-Gutierrez R, Russ HA, Demangel C, Qi L, Tsai B, Liu M, Arvan P. J Biol Chem 299 104836 (2023)
  31. PKR-mediated stress response enhances dengue and Zika virus replication. Ricciardi-Jorge T, da Rocha EL, Gonzalez-Kozlova E, Rodrigues-Luiz GF, Ferguson BJ, Sweeney T, Irigoyen N, Mansur DS. mBio 14 e0093423 (2023)
  32. Perspective: Modulating the integrated stress response to slow aging and ameliorate age-related pathology. Derisbourg MJ, Hartman MD, Denzel MS. Nat Aging 1 760-768 (2021)
  33. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. Mol Cell 82 1107-1122.e7 (2022)
  34. Remodeling the cellular stress response for enhanced genetic code expansion in mammalian cells. Sushkin ME, Koehler C, Lemke EA. Nat Commun 14 6931 (2023)
  35. Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure. Zou Y, Yuan Z, Sun Y, Zhai M, Tan Z, Guan R, Aschner M, Luo W, Zhang J. Oxid Med Cell Longev 2022 3627026 (2022)
  36. Role of Activating Transcription Factor 4 in Murine Choroidal Neovascularization Model. Yasuda H, Tanaka M, Nishinaka A, Nakamura S, Shimazawa M, Hara H. Int J Mol Sci 22 8890 (2021)
  37. Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans. Yashin AI, Wu D, Arbeev K, Yashkin AP, Akushevich I, Bagley O, Duan M, Ukraintseva S. J Transl Genet Genom 5 357-379 (2021)
  38. Switching on stress. Kashiwagi K, Ito T. Nat Chem Biol (2023)
  39. Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells. Dudka W, Hoser G, Mondal SS, Turos-Korgul L, Swatler J, Kusio-Kobialka M, Wołczyk M, Klejman A, Brewinska-Olchowik M, Kominek A, Wiech M, Machnicki MM, Seferynska I, Stoklosa T, Piwocka K. BMC Cancer 22 1254 (2022)
  40. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer. Ghaddar N, Wang S, Woodvine B, Krishnamoorthy J, van Hoef V, Darini C, Kazimierczak U, Ah-Son N, Popper H, Johnson M, Officer L, Teodósio A, Broggini M, Mann KK, Hatzoglou M, Topisirovic I, Larsson O, Le Quesne J, Koromilas AE. Nat Commun 12 4651 (2021)
  41. Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B. Schoof M, Wang L, Cogan JZ, Lawrence RE, Boone M, Wuerth JD, Frost A, Walter P. Nat Commun 12 7103 (2021)
  42. eIF2B-capturing viral protein NSs suppresses the integrated stress response. Kashiwagi K, Shichino Y, Osaki T, Sakamoto A, Nishimoto M, Takahashi M, Mito M, Weber F, Ikeuchi Y, Iwasaki S, Ito T. Nat Commun 12 7102 (2021)
  43. eIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells. Gupta M, Walters BA, Katsara O, Granados Blanco K, Geter PA, Schneider RJ. Proc Natl Acad Sci U S A 120 e2207898120 (2023)


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