Isg15, also known as ubiquitin cross-reactive protein (UCRP), is an interferon-stimulated gene product. It encodes a ubiquitin-like protein that is crucial in the host response to viral infection, being a central player in the antiviral immunity induced by type I interferons [1,2,3,4,5,6]. It can function both as a post-translational modifier through a process called ISGylation, similar to ubiquitylation, and as a "cytokine-like" molecule [3]. Its expression is induced by interferons, and it is involved in multiple cellular responses contributing to the antiviral state, as well as other cellular processes like immune response modulation and damage-repair response [1].

In pressure overload-induced heart failure, cardiac macrophages induce an IFN response in cardiomyocytes, upregulating Isg15. Isg15 deficiency in mice with transverse aortic constriction preserved cardiac function and led to improved ex vivo heart recovery. It was found that Isg15 regulates cardiac amino acid metabolism, and its deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy, suggesting that Isg15 upregulation may contribute to heart failure development by altering cardiomyocyte protein turnover [7]. In humans, individuals born with inactivating mutations of Isg15 do not show an overt viral phenotype but are highly susceptible to environmental mycobacteria and have auto-inflammatory disease presentations. In vitro, Isg15 deficiency leads to persistently high levels of type I IFN-stimulated gene expression and increased resistance to tested viruses, indicating that Isg15 deficiency may increase antiviral responses in humans, contrary to what is expected from mouse experiments [8].

In conclusion, Isg15 has diverse functions, mainly in antiviral immunity but also in other biological processes such as heart function-related metabolism and protein turnover. Studies using Isg15-deficient mouse models have provided insights into its role in heart failure and have also revealed species-specific differences in its function, especially in relation to antiviral responses and susceptibility to certain infections. These findings contribute to our understanding of the complex role of Isg15 in health and disease.

References:

1. Perng, Yi-Chieh, Lenschow, Deborah J. . ISG15 in antiviral immunity and beyond. In Nature reviews. Microbiology, 16, 423-439. doi:10.1038/s41579-018-0020-5. https://pubmed.ncbi.nlm.nih.gov/29769653/

2. Mirzalieva, Oygul, Juncker, Meredith, Schwartzenburg, Joshua, Desai, Shyamal. 2022. ISG15 and ISGylation in Human Diseases. In Cells, 11, . doi:10.3390/cells11030538. https://pubmed.ncbi.nlm.nih.gov/35159348/

3. Sarkar, Lucky, Liu, GuanQun, Gack, Michaela U. 2023. ISG15: its roles in SARS-CoV-2 and other viral infections. In Trends in microbiology, 31, 1262-1275. doi:10.1016/j.tim.2023.07.006. https://pubmed.ncbi.nlm.nih.gov/37573184/

4. Dzimianski, John V, Scholte, Florine E M, Bergeron, Éric, Pegan, Scott D. 2019. ISG15: It's Complicated. In Journal of molecular biology, 431, 4203-4216. doi:10.1016/j.jmb.2019.03.013. https://pubmed.ncbi.nlm.nih.gov/30890331/

5. Freitas, Brendan T, Scholte, Florine E M, Bergeron, Éric, Pegan, Scott D. 2020. How ISG15 combats viral infection. In Virus research, 286, 198036. doi:10.1016/j.virusres.2020.198036. https://pubmed.ncbi.nlm.nih.gov/32492472/

6. Munnur, Deeksha, Banducci-Karp, Adrianna, Sanyal, Sumana. . ISG15 driven cellular responses to virus infection. In Biochemical Society transactions, 50, 1837-1846. doi:10.1042/BST20220839. https://pubmed.ncbi.nlm.nih.gov/36416643/

7. Yerra, Veera Ganesh, Batchu, Sri Nagarjun, Kaur, Harmandeep, Connelly, Kim A, Advani, Andrew. 2023. Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure. In The Journal of clinical investigation, 133, . doi:10.1172/JCI161453. https://pubmed.ncbi.nlm.nih.gov/37115698/

8. Hermann, Mark, Bogunovic, Dusan. 2016. ISG15: In Sickness and in Health. In Trends in immunology, 38, 79-93. doi:10.1016/j.it.2016.11.001. https://pubmed.ncbi.nlm.nih.gov/27887993/