Zhang Mengdi, Li Jingxian, Yan Haiyan, Huang Jun, Wang Fangwei, Liu Ting, Zeng Linghui, Zhou Fangfang
School of Medicine, Zhejiang University City College, Hangzhou, China.
MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Front Cell Dev Biol. 2021 Nov 25;9:788410. doi: 10.3389/fcell.2021.788410. eCollection 2021.
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.
干扰素刺激基因15（ISG15）蛋白是一种由干扰素或病原体诱导产生的类泛素蛋白。ISG15可以以游离形式存在，也可以通过酶促级联反应与靶蛋白共价结合，这一过程被称为ISGylation。已发现ISGylation在I型干扰素诱导的先天免疫反应中发挥重要作用，因此对于宿主细胞抵御RNA、DNA和逆转录病毒至关重要。通过与宿主和病毒靶蛋白共价结合，ISG15抑制病毒颗粒的释放，阻碍病毒复制，并调节病毒的潜伏期，从而发挥强大的抗病毒作用。新型冠状病毒2型木瓜样蛋白酶是一种病毒编码的去泛素化酶，已证明其对泛素和ISG15链偶联均有活性，因此对宿主抗病毒先天免疫反应起抑制作用。在此我们综述了在理解ISG15型类泛素修饰方面的最新研究进展，重点关注其潜在分子机制。我们为进一步研究ISG15在抗病毒免疫中的作用提供全面参考，这可能有助于开发新的抗病毒药物。
