Isg15, also known as ubiquitin cross-reactive protein (UCRP), is an interferon-stimulated gene. It encodes a ubiquitin-like protein and is a key player in the host antiviral response. The host's reaction to viral infection involves type I interferons, which upregulate hundreds of interferon-stimulated genes including Isg15. Free Isg15 protein can conjugate to cellular proteins via ISGylation, an enzymatic cascade similar to ubiquitylation. It also functions as an intracellular and extracellular signaling molecule, modulating the immune response and playing roles in various biological pathways [1,4].

In pressure overload-induced heart failure, Isg15 is upregulated in mouse models with transverse aortic constriction or other relevant treatments. Isg15 deficiency in these mice preserves cardiac function and leads to improved heart recovery ex vivo, suggesting that Isg15 may contribute to heart failure development by altering cardiomyocyte protein turnover [2]. In humans, individuals with inactivating mutations of Isg15 (a form of in vivo loss-of-function model) do not show an overt viral phenotype but are highly susceptible to environmental mycobacteria and have autoinflammatory disease presentations. In vitro, Isg15-deficient human cells show persistently high levels of type I interferon-stimulated gene expression and increased resistance to viruses, indicating differences in the role of Isg15 between species compared to mouse experiments [3].

In conclusion, Isg15 is crucial in the host antiviral response and immune modulation. Mouse models, especially those with Isg15 deficiency, have provided insights into its role in heart failure development. In humans, the study of individuals with Isg15 inactivating mutations reveals its unexpected relationship with susceptibility to mycobacteria and autoinflammatory diseases, highlighting the importance of understanding Isg15 function across species for potential therapeutic implications.