{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:21:23Z","timestamp":1788448883477,"version":"build-2803163510"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>ISGylation is an interferon-inducible ubiquitin-like post-translational modification mediated by the interferon-stimulated gene 15 conjugation system. Initially characterized as an antiviral effector pathway, ISGylation is now increasingly recognized as a regulator of organelle homeostasis and cellular stress responses. This review summarizes emerging evidence linking ISG15-related mechanisms and covalent ISGylation to major organelle systems, including mitochondria, the endoplasmic reticulum\u2013Golgi axis, endolysosomal compartments, ribosome-associated translation, and lipid droplets. We distinguish covalent ISGylation from free ISG15 signaling and ubiquitin specific protease 18-mediated interferon regulation, and further classify existing findings into evidence-based levels ranging from substrate-validated modification to correlative interferon signatures. At the mitochondrial level, direct and pathway-level evidence implicates ISG15 biology in DRP1-mediated fission, MFN1\/2-associated mitophagy, oxidative metabolism, and redox regulation; direct effects of MFN1\/2 ISGylation on mitochondrial fusion remain unproven. Along the ER\u2013Golgi axis, ISG15-related pathways intersect with unfolded protein response signaling, endoplasmic reticulum-associated degradation, and stimulator of interferon genes-mediated innate immune activation. In the endolysosomal system, ISGylation and ISG15-associated pathways modulate autophagic flux, multivesicular body fate, and exosome secretion in a context-dependent manner. Ribosome-associated co-translational ISGylation links nascent protein surveillance with antiviral defense, whereas lipid droplet-associated ISG15\/ISGylation pathways are linked to lipid metabolism and immune signaling. Current evidence supports an organelle-centered view of ISG15 biology but indicates that validated covalent mechanisms remain confined to selected substrates and contexts. Clinical translation will require organelle-resolved ISGylome mapping, substrate-level validation, and standardized biomarker assays before context-selective targeting can be considered.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1960492","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:53:12Z","timestamp":1788447192000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhuoer","family":"Li","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2010.0110","article-title":"Interferon-stimulated gene 15 and the protein ISGylation system","volume":"31","author":"Zhang","year":"2011","journal-title":"J Interferon Cytokine 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