TRIM proteins in autophagy-mediated antiviral defense

先天性免疫系统是宿主抵抗入侵的病毒病原体的第一防御机制。它通过诱导抗病毒细胞因子，最突出的是I型干扰素（IFN），随后导致大量抗病毒蛋白的基因表达，从而起到快速反应的作用。此外，先天免疫系统刺激适应性免疫应答以促进感染的清除。最近的证据表明，先天免疫系统的信号通路与自噬密切相关并受其调节。自噬作为抗病毒天然免疫防御中的一种重要的细胞内在机制已越来越受到人们的重视。自噬的缺陷已被证明对病原体感染的易感性有积极影响，事实上，许多病毒在感染细胞后诱导自噬反应，包括重要的人类病原体甲型流感病毒（IAV）。 该项目的目标是确定新的细胞因子介导的自噬诱导响应IAV感染，并表征这些因素在抗病毒先天免疫中的生理作用。TRIM蛋白是IFN介导的抗病毒天然免疫中的一类重要分子。此外，最近有报道称，TRIM蛋白在调节自噬中发挥作用;然而，TRIM蛋白诱导自噬对抗病毒免疫防御的确切作用和影响是完全未知的。有趣的是，如初步数据所示，几种TRIM蛋白，特别是TRIM 25，在特异性病毒诱导的自噬中发挥作用。为了系统地确定TRIM蛋白在病毒诱导的自噬中的作用，申请人将筛选靶向所有已知人TRIM蛋白的shRNA文库，用于在IAV感染期间调节自噬。鉴定的自噬调节TRIM蛋白将进一步表征其功能结构域、自噬激活模式及其相互作用伴侣。随后，将分析它们在细胞内在抗IAV和其他病毒的抗病毒防御中的生理作用。对TRIM介导的自噬及其在IFN应答中的作用之间的相互作用以及其自噬依赖的抗病毒活性的新见解，将有助于在机械深度上描绘自噬作为先天抗病毒防御机制的作用。

The innate immune system is the first defense mechanism of a host against invading viral pathogens. It serves as a quick response by inducing antiviral cytokines, most prominently type-I interferons (IFNs), which subsequently lead to the gene expression of a large variety of antiviral proteins. In addition, the innate immune system stimulates the adaptive immune response to facilitate clearance of an infection. Recent evidence indicates that signaling pathways of the innate immune system are tightly interconnected with and regulated by autophagy. Autophagy has been increasingly appreciated as a critical cell-intrinsic mechanism in the antiviral innate immune defense. Defects in autophagy have been shown to positively influence the susceptibility to pathogen infections, and in fact, many viruses induce an autophagic response upon infecting a cell, including the important human pathogen influenza A virus (IAV). The goal of this project is to identify novel cellular factors mediating autophagy induction in response to IAV infection and to characterize these factors with respect to their physiological role in antiviral innate immunity. Tripartite motif (TRIM) proteins have emerged as an important class of molecules in IFN-mediated antiviral innate immunity. Furthermore, it has been recently reported that TRIM proteins play roles in regulating autophagy; however, the exact role and impact of autophagy induction by TRIM proteins on antiviral immune defenses are completely unknown. Intriguingly, as shown in the preliminary data, several TRIM proteins, and in particular TRIM25, play a role in specifically virus-induced autophagy. To systematically determine the role of TRIM proteins in virus-induced autophagy, the applicant will screen a shRNA library targeting all known human TRIM proteins for modulation of autophagy during infection with IAV. The identified autophagy-modulating TRIM proteins will be further characterized regarding their functional domains, their modes of autophagy activation, and their interaction partners. Subsequently, their physiological role in the cell-intrinsic antiviral defense against IAV and other viruses will be analyzed. New insights into the interplay between TRIM-mediated autophagy and their roles in the IFN response, as well as into their autophagy-dependent antiviral activities, will help to delineate in mechanistic depth the role of autophagy as an innate antiviral defense mechanism.