Interferon-stimulated gene 15 (ISG15) is a pivotal protein involved in antiviral defense and immune regulation. This study presents a remarkable case series of a consanguineous family with a homozygous variant in the ISG15 gene, leading to a complex interplay of intriguing dermatological manifestations and concurrent zinc deficiency. The range of cutaneous phenotypes observed in the family members, from severe ulcerative lesions to atopic dermatitis, highlights the intricate relationship between the identified genetic variant and dermatological conditions. Furthermore, zinc deficiency adds another layer of complexity to the understanding of these conditions. Comprehensive assessments of zinc levels were conducted for three siblings, while the fourth sibling\'s evaluation was impeded. This extraordinary case series offers a unique opportunity for scientific exploration, shedding light on complex genetic disorders and potentially paving the way for novel diagnostic and therapeutic strategies in medical science. The convergence of familial genetics, the homozygous ISG15 variant, and the captivating spectrum of cutaneous manifestations hold promise for advancing our understanding of these conditions and their underlying mechanisms.

The interferon-stimulating gene 15 (ISG15) protein is a ubiquitin-like protein induced by interferons or pathogens. ISG15 can exist in free form or covalently bind to the target protein through an enzymatic cascade reaction, which is called ISGylation. ISGylation has been found to play an important role in the innate immune responses induced by type I interferon, and is, thus, critical for the defense of host cells against RNA, DNA, and retroviruses. Through covalent binding with the host and viral target proteins, ISG15 inhibits the release of viral particles, hinder viral replication, and regulates the incubation period of viruses, thereby exerting strong antiviral effects. The SARS-CoV-2 papain-like protease, a virus-encoded deubiquitinating enzyme, has demonstrated activity on both ubiquitin and ISG15 chain conjugations, thus playing a suppressive role against the host antiviral innate immune response. Here we review the recent research progress in understanding ISG15-type ubiquitin-like modifications, with an emphasis on the underlying molecular mechanisms. We provide comprehensive references for further studies on the role of ISG15 in antiviral immunity, which may enable development of new antiviral drugs.