Interferon‐induced protein ISG15 in the central nervous system, quo vadis?

The ubiquitin‐like interferon (IFN)‐stimulated gene 15 (ISG15) is a unique molecular effector that functions both intra‐ and extracellularly. Central to its pleiotropic nature is the ability to coordinate cellular responses following its conjugation to target proteins via ISGylation or in its free form. The activity of ISG15 is highly context‐dependent: in the case of viral infections, ISG15 can serve as a pro‐ or antiviral factor. While ISG15 has been studied extensively, several gaps persist in our understanding of its role in dysregulated immune homeostasis. In particular, the role of ISG15 in the central nervous system (CNS), which has traditionally been considered an immune‐privileged site, remains ill‐defined. Interestingly, elevated ISG15 expression is observed in the CNS following instances of brain injury, autoimmunity, neurodegeneration, and viral infection. In this review, we seek to provide a comprehensive analysis of these studies as they pertain to ISG15 and its potential roles in the CNS. Furthermore, we discuss questions and challenges in the field while highlighting ISG15 as a potential diagnostic biomarker or therapeutic target. Impact statement While ISG15 has been studied extensively, several gaps remain in our understanding of its role in dysregulated immune homeostasis and its impact within the central nervous system (CNS). In this review, we provide a comprehensive analysis of the emerging roles of ISG15 in brain injury, autoimmunity, neurodegeneration, and viral infection within the CNS.