Ali Mudassir S, Tang Yun Sang, Lee Horace Hok Yeung, Baker Susan C, Mok Chris Ka Pun
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Chicago, Maywood, IL, 60153, USA.
Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.
Cell Mol Life Sci. 2025 Jul 28;82(1):289. doi: 10.1007/s00018-025-05705-w.
Interferon-stimulated gene 15 (ISG15) is an interferon-stimulated gene and a ubiquitin-like protein, traditionally known for its role in ISGylation. In addition to its intracellular functions, recent studies have revealed a novel role for extracellular ISG15, particularly in the context of viral infections. Beyond type I interferons, various stimuli, including viral and bacterial infections, have been found to trigger its secretion. Notably, the integrin receptor LFA-1 has been identified as a receptor for extracellular ISG15. Despite these advancements, the precise mechanisms by which extracellular ISG15 functions-such as the pathways regulating its secretion and receptor interactions-remain unclear. Viral proteins and de-ISGylating enzymes are known to influence ISG15 secretion levels, thereby impacting its immunomodulatory potential. This mini-review summarizes the existing studies aimed at understanding the mechanisms behind the secretion and functions of extracellular ISG15, with a particular focus on its immunomodulatory effects during infection. We also explore the contrasting roles of extracellular ISG15 in mice and humans, highlighting the need for more species-specific research. Further investigation into the role of extracellular ISG15 may uncover novel therapeutic strategies for infectious diseases, cancer, and inflammatory conditions.
干扰素刺激基因15（ISG15）是一种干扰素刺激基因，也是一种类泛素蛋白，传统上以其在ISGylation中的作用而闻名。除了其细胞内功能外，最近的研究还揭示了细胞外ISG15的新作用，特别是在病毒感染的背景下。除了I型干扰素外，包括病毒和细菌感染在内的各种刺激都被发现会触发其分泌。值得注意的是，整合素受体LFA-1已被确定为细胞外ISG15的受体。尽管有这些进展，但细胞外ISG15发挥作用的精确机制，如调节其分泌和受体相互作用的途径，仍不清楚。已知病毒蛋白和去ISGylation酶会影响ISG15的分泌水平，从而影响其免疫调节潜力。这篇综述总结了旨在了解细胞外ISG15分泌和功能背后机制的现有研究，特别关注其在感染期间的免疫调节作用。我们还探讨了细胞外ISG15在小鼠和人类中的不同作用，强调了开展更多物种特异性研究的必要性。对细胞外ISG15作用的进一步研究可能会揭示针对传染病、癌症和炎症性疾病的新治疗策略。
