{"entity": "researcher", "timestamp": "2026-08-20T21:24:15.461Z", "family": "Schaffer", "given": "Ashleigh", "initials": "A", "orcid": "0000-0002-1164-697X", "affiliations": ["Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c283750c40b41b7959efe3f42c9ccad.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c283750c40b41b7959efe3f42c9ccad"}}, "publications": [{"entity": "publication", "iuid": "a312b3ce8eec4855b16873537f95a8bb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a312b3ce8eec4855b16873537f95a8bb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a312b3ce8eec4855b16873537f95a8bb"}}, "title": "Plasticity of the mammalian integrated stress response.", "authors": [{"family": "Chen", "given": "Chien-Wen", "initials": "CW", "orcid": "0000-0002-1214-4058", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/31bfc8f68c7f46c184b233efccd23651.json"}}, {"family": "Papadopoli", "given": "David", "initials": "D"}, {"family": "Szkop", "given": "Krzysztof J", "initials": "KJ"}, {"family": "Guan", "given": "Bo-Jhih", "initials": "BJ"}, {"family": "Alzahrani", "given": "Mohammed", "initials": "M", "orcid": "0000-0001-7291-5275", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2b8c5964a93e47eea6601cc9b13ae343.json"}}, {"family": "Wu", "given": "Jing", "initials": "J", "orcid": "0009-0000-5199-1199", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ac7a88e311aa495a93825a2a7065da88.json"}}, {"family": "Jobava", "given": "Raul", "initials": "R"}, {"family": "Asraf", "given": "Mais M", "initials": "MM"}, {"family": "Krokowski", "given": "Dawid", "initials": "D"}, {"family": "Vourekas", "given": "Anastasios", "initials": "A", "orcid": "0000-0002-1850-5635", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/85a3939de7c341b084bb7293bfb505b9.json"}}, {"family": "Merrick", "given": "William C", "initials": "WC"}, {"family": "Komar", "given": "Anton A", "initials": "AA"}, {"family": "Koromilas", "given": "Antonis E", "initials": "AE", "orcid": "0000-0003-1972-0799", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7825afc7ac8942819083ce7c570b5508.json"}}, {"family": "Gorospe", "given": "Myriam", "initials": "M", "orcid": "0000-0001-5439-3434", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f959a00a1c6d406892d949aeafed5a4f.json"}}, {"family": "Payea", "given": "Matthew J", "initials": "MJ", "orcid": "0000-0002-1960-4563", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7127b888bae44cd59c2e1d60eff38366.json"}}, {"family": "Wang", "given": "Fangfang", "initials": "F"}, {"family": "Clayton", "given": "Benjamin L L", "initials": "BLL", "orcid": "0000-0001-9552-404X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7d27aa75b2e84ddf8c7ac065d22db7fd.json"}}, {"family": "Tesar", "given": "Paul J", "initials": "PJ", "orcid": "0000-0003-1532-3155", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2126dba093aa4bfd8ed62c630333452e.json"}}, {"family": "Schaffer", "given": "Ashleigh", "initials": "A", "orcid": "0000-0002-1164-697X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c283750c40b41b7959efe3f42c9ccad.json"}}, {"family": "Miron", "given": "Alexander", "initials": "A"}, {"family": "Bederman", "given": "Ilya", "initials": "I", "orcid": "0000-0002-1909-5746", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d234b19b68564c858dbc42c1f5adf9b1.json"}}, {"family": "Jankowsky", "given": "Eckhard", "initials": "E"}, {"family": "Vogel", "given": "Christine", "initials": "C", "orcid": "0000-0002-2856-3118", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/175408d95b194f04a8e8cdaf90c20933.json"}}, {"family": "Val\u00e1\u0161ek", "given": "Leo\u0161 Shivaya", "initials": "LS", "orcid": "0000-0001-8123-8667", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a73e4c57d07b45188685deb3fbe83043.json"}}, {"family": "Dinman", "given": "Jonathan D", "initials": "JD", "orcid": "0000-0002-2402-9698", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/947f8aa98d194d94bdb33b6f4fce1c30.json"}}, {"family": "Zhang", "given": "Youwei", "initials": "Y", "orcid": "0000-0003-0011-7922", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/926e555efbff4fbd97f028680d69a960.json"}}, {"family": "Tirosh", "given": "Boaz", "initials": "B"}, {"family": "Larsson", "given": "Ola", "initials": "O", "orcid": "0000-0003-1412-1308", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3f81c6cbbe564d38bc78d1af5153d804.json"}}, {"family": "Topisirovic", "given": "Ivan", "initials": "I", "orcid": "0000-0002-5510-9762", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1bca1813f34c4864940ac6593044a9cc.json"}}, {"family": "Hatzoglou", "given": "Maria", "initials": "M", "orcid": "0000-0003-2037-1231", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3fbc5330f8c84c548a8472bb81cf77f3.json"}}], "type": "journal article", "published": "2025-05-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "641", "issue": "8065", "pages": "1319-1328", "issn-l": "0028-0836"}, "abstract": "An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-\u03b1 (eIF2\u03b1, encoded by EIF2S1; eIF2\u03b1-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2\u03b1-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2\u03b1-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.", "doi": "10.1038/s41586-025-08794-6", "pmid": "40140574", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12119373"}, {"db": "pii", "key": "10.1038/s41586-025-08794-6"}], "notes": [], "created": "2026-08-20T08:59:09.414Z", "modified": "2026-08-20T08:59:10.076Z"}]}