ISG15 Is a Key Multidirectional Regulator of Cytosolic RNA- and DNA-Sensing Pathways and Type I Interferon Feedback Loops.

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.