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Sci.","IJMS"],"abstract":"<jats:p>Activation of cytosolic RNA and DNA sensing pathways that normally recognize viral nucleic acids triggers the expression and release of type I interferons (IFN-I). This release drives the expression of interferon-stimulated genes (ISGs) that activate acute inflammation and counteract viral replication at various stages. Recent studies have highlighted how interferon-stimulated gene 15 (ISG15), a small, ubiquitin-like modifier, regulates cytosolic RNA and DNA sensing pathway proteins to control the antiviral response and inflammation. ISG15 is a multifunctional protein that acts as a secreted cytokine, binds freely to intracellular proteins, and covalently modifies proteins in a reversible process termed ISGylation. A dual regulatory molecule, ISG15 can both stabilize and destabilize proteins that promote and inhibit IFN-I signaling. Conversely, viruses have evolved strategies to disrupt and exploit ISG15-dependent antiviral responses to evade the host immune system. In this review, we examine how ISG15 regulates cytosolic RNA and DNA sensing pathway proteins to control IFN-I signaling and the antiviral response, highlighting it as a master regulator that fine-tunes IFN-I signaling and feedback. Recognizing the multifaceted action of ISG15 is essential for designing balanced therapeutic strategies across antiviral drug development, cancer immunotherapy, and chronic inflammatory disease management.<\/jats:p>","DOI":"10.3390\/ijms27198837","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:31:31Z","timestamp":1791203491000},"page":"8837","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ISG15 Is a Key Multidirectional Regulator of Cytosolic RNA- and DNA-Sensing Pathways and Type I Interferon Feedback Loops"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9869-5688","authenticated-orcid":false,"given":"Maleana G.","family":"White","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9279-8755","authenticated-orcid":false,"given":"Sergey","family":"Iordanskiy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1600-065X.2012.01146.x","article-title":"PAMPs and DAMPs: Signal 0s that spur autophagy and immunity","volume":"249","author":"Tang","year":"2012","journal-title":"Immunol. 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