{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:19:58Z","timestamp":1790835598208,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012203","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01EY020866 and R35GM148357"],"award-info":[{"award-number":["R01EY020866 and R35GM148357"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially translating the transcription factor ATF4, a process regulated by upstream open reading frames (uORFs) in its 5\u2019 leader. In\n                    <jats:italic>Drosophila,<\/jats:italic>\n                    Xrp1 is another transcription factor induced during the ISR, but the precise underlying mechanism remains unclear. Here, we report that Xrp1 induction in response to ER stress is regulated by both its uORFs and the main ORF sequence.\n                    <jats:italic>Xrp1<\/jats:italic>\n                    has seven splice isoforms, and the two predominant transcripts expressed in eye imaginal discs contain uORFs. Expressing the ER stress-imposing\n                    <jats:italic>ninaE<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G69D<\/jats:italic>\n                    <\/jats:sup>\n                    transgene in this tissue induced\n                    <jats:italic>Xrp1<\/jats:italic>\n                    expression without significantly changing the\n                    <jats:italic>Xrp1<\/jats:italic>\n                    splice isoform composition. The uORF-containing 5\u2019 leaders, particularly the AUG codon of the second uORF, inhibited DsRed expression when placed upstream of the reporter. Unlike ATF4, the uORF-containing 5\u2019 leader alone was insufficient to mediate the main ORF induction, but Xrp1 induction occurred in\n                    <jats:italic>ninaE<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G69D<\/jats:italic>\n                    <\/jats:sup>\n                    -expressing discs when Xrp1\u2019s 5\u2019 leader and the main ORF sequence were both present. Functionally,\n                    <jats:italic>Xrp1<\/jats:italic>\n                    was required to maintain the integrity of\n                    <jats:italic>Drosophila<\/jats:italic>\n                    photoreceptors exposed to constant light. In a different disease model,\n                    <jats:italic>parkin<\/jats:italic>\n                    mutants activated\n                    <jats:italic>Xrp1<\/jats:italic>\n                    target gene expression in specific tissues and\n                    <jats:italic>Xrp1<\/jats:italic>\n                    loss enhanced the viability of\n                    <jats:italic>parkin<\/jats:italic>\n                    mutant flies during adult eclosion. These results provide molecular and pathological insights into\n                    <jats:italic>Xrp1<\/jats:italic>\n                    regulation and function in disease models.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012203","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T17:47:48Z","timestamp":1781113668000},"page":"e1012203","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0449-230X","authenticated-orcid":true,"given":"Hidetaka","family":"Katow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thao","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Hyunsoh","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1046-535X","authenticated-orcid":true,"given":"Hyung Don","family":"Ryoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"issue":"4","key":"pgen.1012203.ref001","doi-asserted-by":"crossref","first-page":"107151","DOI":"10.1016\/j.jbc.2024.107151","article-title":"The integrated stress response in metabolic 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Vasudevan","year":"2022","journal-title":"Dis Model Mech"},{"issue":"1","key":"pgen.1012203.ref005","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41467-025-67357-5","article-title":"4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila","volume":"17","author":"K Walsh","year":"2025","journal-title":"Nat Commun"},{"key":"pgen.1012203.ref006","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.38752","article-title":"Adaptation to constant light requires Fic-mediated AMPylation of BiP to protect against reversible photoreceptor degeneration","volume":"7","author":"AT Moehlman","year":"2018","journal-title":"Elife"},{"issue":"4","key":"pgen.1012203.ref007","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/ncb2447","article-title":"CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model","volume":"14","author":"M-J 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