A novel TRIM protein involved in innate immunity

描述（由申请人提供）：TRIM 5作为决定人类免疫缺陷病毒（HIV）的跨物种限制的因子的发现已经引起了对TRIM家族的E3连接酶的相当大的兴趣，所述TRIM家族包括其它抗病毒蛋白，例如TRIM 19、TRIM 22、TRIM 25和TRIM 28。鉴于TRIM蛋白家族的许多成员在对干扰素的反应中被上调，我们决定系统地测试它们的抗逆转录病毒活性。将表达筛选与靶向RNAi实验相结合，我们鉴定了约20种表现出复杂抗病毒活性的TRIM蛋白（Uchil et al.，2008年）。我们推测，一些观察到的抗病毒活性是由于TRIM蛋白在先天免疫中的一般作用。TRIM 25等蛋白质的表达触发先天免疫信号级联，导致建立抗病毒状态。为了鉴定类似地参与先天免疫的新型TRIM蛋白，我们筛选了所有55种蛋白激活或负调节NF κ B、AP-1和I型干扰素信号传导途径的能力。我们的工作确定了一些额外的炎症和先天免疫效应蛋白NF κ B的正调节因子。在这里，我们建议研究这些蛋白质，似乎在Toll样受体（TLR）信号转导中发挥重要作用。具体来说，我们将测试其在TLR 4信号传导中的潜在作用，包括在缺乏该蛋白的小鼠中，并开始研究该蛋白调节先天免疫的分子机制。确定这种新型TRIM蛋白的细胞功能是了解其抗病毒特性的先决条件。 公共卫生相关性：以前，我们鉴定了20种TRIM E3连接酶蛋白与复杂的抗病毒蛋白。在这里，我们建议研究这些蛋白质在先天免疫信号转导的潜在作用。确定其细胞功能是了解其抗病毒特性的先决条件。

DESCRIPTION (provided by applicant): The discovery of TRIM5 as a factor determining cross-species restriction of the human immunodeficiency virus (HIV) has prompted considerable interest in the TRIM family of E3 ligases that includes other antiviral proteins such as TRIM19, TRIM22, TRIM25 and TRIM28. Given that many members of the TRIM family of proteins are up-regulated in response to interferons, we decided to systematically test their anti-retroviral activities. Combining an expression screen with targeted RNAi experiments, we identified ~20 TRIM proteins that exhibit complex antiviral activities (Uchil et al., 2008). We hypothesize that some of the observed antiviral activities are due to general roles of TRIM proteins in innate immunity. Expression of proteins such as TRIM25 triggers innate immunity signaling cascades that lead to the establishment of an antiviral state. To identify novel TRIM proteins similarly involved in innate immunity, we screened all 55 proteins for their ability to activate or negatively regulate NFkB, AP-1 and type I interferon signaling pathways. Our work identified a number of additional positive regulators of the inflammatory and innate immunity effector protein NFkB. Here we propose to study one of these proteins that appears to play an important role in toll-like receptor (TLR) signaling. Specifically, we will test its potential role in TLR4 signaling, including in mice lacking the protein and initiate the investigation of the molecular mechanism by which this protein regulates innate immunity. Determining the cellular function of this novel TRIM protein is a prerequisite to understand how it manifests its antiviral properties. PUBLIC HEALTH RELEVANCE: Previously, we identified 20 TRIM E3 ligases proteins with complex antiviral proteins. Here we propose to study the potential role of one of these proteins in innate immunity signaling. Determining its cellular function is a prerequisite to understand how it manifests its antiviral properties.