Isg15, also known as ubiquitin cross-reactive protein (UCRP), is an interferon-stimulated gene product. It encodes a ubiquitin-like protein that is a key component of the host response to viral infection [1,2,3,4,5,6]. The host's response to viral infection involves the induction of type I interferons, which leads to the upregulation of Isg15. Isg15 can function both as a post-translational modifier, through a process called ISGylation similar to ubiquitylation, and as a "cytokine-like" molecule [1,2,3,6]. It plays diverse roles in modulating the host antiviral response, immune response, and other host signaling pathways [1].

In the context of disease, Isg15 deficiency in humans presents a different phenotype compared to mouse models. While Isg15 has antiviral functions in mice, humans with inactivating mutations of Isg15 are highly susceptible to environmental mycobacteria and have autoinflammatory disease presentations, yet show increased resistance to tested viruses in vitro [8]. In heart failure, pressure overload induces Isg15, which contributes to adverse ventricular remodeling by altering cardiomyocyte protein turnover [7]. In lung adenocarcinoma, Isg15 targets glycosylated PD-L1, promotes its degradation, and enhances antitumor immune effects [9].

In conclusion, Isg15 is a multifunctional protein involved in the host's response to viral infections and various disease conditions. Mouse models have been valuable in understanding its antiviral functions, while human studies with Isg15-deficient individuals have revealed unexpected differences in its role in immunity and disease susceptibility. The study of Isg15 provides insights into host-pathogen interactions, immune regulation, and disease mechanisms [1,7,8,9].

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/

9. Qu, Tongyuan, Zhang, Wenshuai, Yan, Chenhui, Zhao, Qiang, Cao, Wenfeng. 2023. ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma. In Journal of translational medicine, 21, 341. doi:10.1186/s12967-023-04135-1. https://pubmed.ncbi.nlm.nih.gov/37217923/