ISG15 Is a Key Multidirectional Regulator of Cytosolic RNA- and DNA-Sensing Pathways and Type I Interferon Feedback Loops
- 1Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- 2Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
- 3Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
Abstract
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.
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BibTeX
@article{white2026isg15,
title = {{ISG15 Is a Key Multidirectional Regulator of Cytosolic RNA- and DNA-Sensing Pathways and Type I Interferon Feedback Loops}},
author = {Maleana G. White and Sergey Iordanskiy},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198837},
url = {https://www.mdpi.com/1422-0067/27/19/8837},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ISG15 Is a Key Multidirectional Regulator of Cytosolic RNA- and DNA-Sensing Pathways and Type I Interferon Feedback Loops
AU - Maleana G. White
AU - Sergey Iordanskiy
PY - 2026
DA - 2026/10/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198837
UR - https://www.mdpi.com/1422-0067/27/19/8837
AB - 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.
SN - 1422-0067
ER -