Mechanism and Function of ISG15

总结 人ISG15是一种在先天免疫应答中起作用的泛素样蛋白（Ubl）， 具有三种不同的生物化学活性。作为一种泛素样修饰剂，它与 数百种细胞和病毒蛋白质。ISG15的E1、E2、E3和去缀合酶（Ube1L/Uba7， UbcH8/Ube2L6、Herc5和Usp 18），与ISG 15一样，在转录水平上被I型 干扰素（IFN-α/β）信号传导。ISG15的第二个功能是作为细胞外信号蛋白。ISG15是 从许多细胞类型释放到细胞外空间，并向自然杀伤细胞和T细胞发出信号以分泌 IFN-γ，其在对病原体感染的应答中起主要作用。的细胞表面受体 细胞外SG15是LFA-1，一种免疫细胞特异性整联蛋白。人ISG15的第三个功能是， 负调节I型干扰素信号传导，正如一些人发生的I型干扰素病所揭示的那样 ISG15缺陷型患者;人ISG15的这种功能与小鼠ISG15不同。的一个挑战 该领域的目的是了解ISG15的活动是如何调节和时间控制的，以及哪些活动 与对特定病原体的反应密切相关，包括结核分枝杆菌和 SARS-CoV-2.为了进一步了解ISG15在先天免疫应答中的作用， 病原体，这项建议将集中在底物和赖氨酸的选择性的基础上的Herc5/Herc6家族， ISG15连接酶，ISG15诱导的LFA-1下游信号通路，导致细胞因子分泌， 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.