Mechanism and Function of ISG15

摘要 人类ISG15是一种泛素样蛋白(Ubl)，在先天性免疫反应中发挥作用，它是 因具有三种不同的生化活性而引人注目。作为泛素样修饰物，它与 数以百计的细胞和病毒蛋白。ISG15的E1、E2、E3和解偶联酶(Ube1L/Uba7， UbcH8/Ube2L6、Herc5和Usp18)，与ISG15一样，由I型在转录水平上诱导 干扰素(干扰素-α/β)信号传导。ISG15的第二个功能是作为细胞外信号蛋白。ISG15为 从多种细胞类型释放到细胞外空间，并向自然杀伤细胞和T细胞分泌信号 干扰素-γ，在病原体感染的应答中发挥重要作用。细胞表面受体 细胞外SG15是一种免疫细胞特异性整合素LFA-1。人类ISG15的第三个功能是它 负向调节I型干扰素信号，如某些患者出现的I型干扰素病所揭示的那样 ISG15缺乏的患者；人ISG15的这一功能与小鼠ISG15不同。世界上的一个挑战 实地了解ISG15的活动是如何管理和临时控制的，以及哪些活动 与对特定病原体的反应最密切相关，包括结核分枝杆菌和 SARS-CoV-2。为了加深我们对ISG15先天免疫反应的理解 病原体，这项建议将集中在Herc5/Herc6家族的底物和赖氨酸选择性的基础上 ISG15连接酶，ISG15诱导的LFA-1下游的信号通路，导致细胞因子的分泌， 以及ISG15释放到细胞外空间的机制。

SUMMARY Human ISG15 is a ubiquitin-like protein (Ubl) that functions in innate immune responses, and it is remarkable for possessing three distinct biochemical activities. As a ubiquitin-like modifier it is conjugated to hundreds of cellular and viral proteins. The E1, E2, E3, and de-conjugating enzymes for ISG15 (Ube1L/Uba7, UbcH8/Ube2L6, Herc5, and Usp18, respectively), are, like ISG15, induced at the transcriptional level by Type I interferon (IFN-α/β) signaling. A second function of ISG15 is as an extracellular signaling protein. ISG15 is released into the extracellular space from many cell types and signals to Natural Killer and T cells to secrete IFN-γ, which plays a major role in the response to pathogen infections. The cell surface receptor for extracellular SG15 is LFA-1, an immune cell-specific integrin. A third function of human ISG15 is that it negatively regulates Type I IFN signaling, as revealed by the Type I interferonopathy that occurs in some ISG15-deficient patients; this function of human ISG15 is not shared with mouse ISG15. A challenge in the field is to understand how the activities of ISG15 are regulated and temporally controlled and which activities are most closely associated with responses to specific pathogens, including Mycobacterium tuberculosis and SARS-CoV-2. To further our understanding of ISG15 in innate immune responses to these and other pathogens, this proposal will focus on the basis of substrate and lysine selectivity of the Herc5/Herc6 family of ISG15 ligases, the ISG15-induced signaling pathway downstream of LFA-1 that leads to cytokine secretion, and the mechanism by which ISG15 released into the extracellular space.