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A number of different kinases respond to various stresses leading to the phosphorylation of the alpha subunit of eIF2, and collectively this regulation is known as the integrated stress response, ISR. This targeting of eIF2B allows the cell to regulate protein synthesis and reprogramme gene expression to restore homeostasis. Advances within structural biology have furthered our understanding of how eIF2B interacts with eIF2 in both the productive GEF active form and the non-productive eIF2\u03b1 phosphorylated form. Here, current knowledge of the role of eIF2B in the ISR is discussed within the context of normal and disease states focusing particularly on diseases such as vanishing white matter disease (VWMD) and permanent neonatal diabetes mellitus (PNDM), which are directly linked to mutations in eIF2B. The role of eIF2B in synaptic plasticity and memory formation is also discussed. In addition, the cellular localisation of eIF2B is reviewed and considered along with the role of additional in vivo eIF2B binding factors and protein modifications that may play a role in modulating eIF2B activity during health and disease.<\/jats:p>","DOI":"10.1042\/bsr20211699","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T07:25:48Z","timestamp":1652772348000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Regulation and function of elF2B in neurological and metabolic disorders"],"prefix":"10.1042","volume":"42","author":[{"given":"Filipe\u00a0M.","family":"Hanson","sequence":"first","affiliation":[{"name":"Biomolecular Sciences Research Centre, Industry and Innovation Research Institute, Sheffield Hallam University, Sheffield, S1 1WB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel\u00a0E.","family":"Hodgson","sequence":"additional","affiliation":[{"name":"Biomolecular Sciences Research Centre, Industry and Innovation Research Institute, Sheffield Hallam University, Sheffield, S1 1WB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalena\u00a0I.\u00a0Ribeiro","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Biomolecular Sciences Research Centre, Industry and Innovation Research Institute, Sheffield Hallam University, Sheffield, S1 1WB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.\u00a0Elizabeth","family":"Allen","sequence":"additional","affiliation":[{"name":"Biomolecular Sciences Research Centre, Industry and Innovation Research Institute, Sheffield Hallam University, Sheffield, S1 1WB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6740-1445","authenticated-orcid":false,"given":"Susan\u00a0Gerarda","family":"Campbell","sequence":"additional","affiliation":[{"name":"Biomolecular Sciences Research Centre, Industry and Innovation Research Institute, Sheffield Hallam University, Sheffield, S1 1WB, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"2022062010430802400_B1","doi-asserted-by":"publisher","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: from mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"key":"2022062010430802400_B2","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1038\/nature03897","article-title":"Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2","volume":"436","author":"Costa-Mattioli","year":"2005","journal-title":"Nature"},{"key":"2022062010430802400_B3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cell.2006.09.014","article-title":"Dendritic protein synthesis, synaptic plasticity, and memory","volume":"127","author":"Sutton","year":"2006","journal-title":"Cell"},{"key":"2022062010430802400_B4","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.288.5469.1254","article-title":"Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression","volume":"288","author":"Huber","year":"2000","journal-title":"Science"},{"key":"2022062010430802400_B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.05033","article-title":"The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly","volume":"4","author":"Sidrauski","year":"2015","journal-title":"eLife"},{"key":"2022062010430802400_B6","doi-asserted-by":"publisher","first-page":"e42940","DOI":"10.7554\/eLife.42940","article-title":"eIF2B activator prevents neurological defects caused by a chronic integrated stress response","volume":"8","author":"Wong","year":"2019","journal-title":"Elife"},{"key":"2022062010430802400_B7","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/ana.25287","article-title":"Natural History of Vanishing White Matter","volume":"84","author":"Hamilton","year":"2018","journal-title":"Ann. 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