A novel TRIM protein involved in innate immunity

描述(申请人提供)：TRIM5作为决定人类免疫缺陷病毒(HIV)跨物种限制的一个因素的发现，引起了人们对TRIM家族E3连接酶的相当大的兴趣，该家族包括其他抗病毒蛋白，如TRIM19、TRIM22、TRIM25和TRIM28。鉴于TRIM蛋白家族的许多成员对干扰素的反应上调，我们决定系统地测试它们的抗逆转录病毒活性。结合表达筛选和靶向RNAi实验，我们鉴定了大约20种显示复杂抗病毒活性的TRIM蛋白(Uchil等人，2008年)。我们推测，一些观察到的抗病毒活性是由于TRIM蛋白在先天性免疫中的一般作用。TRIM25等蛋白质的表达触发先天免疫信号级联，从而导致抗病毒状态的建立。为了确定与先天免疫相似的新的TRIM蛋白，我们筛选了所有55种蛋白，以了解它们激活或负调控NFkB、AP-1和I型干扰素信号通路的能力。我们的工作确定了炎症和先天免疫效应蛋白NFkB的一些额外的积极调节因子。在这里，我们建议研究其中一个蛋白，它似乎在Toll样受体(TLR)信号转导中发挥重要作用。具体地说，我们将测试其在TLR4信号转导中的潜在作用，包括在缺乏该蛋白的小鼠中，并启动该蛋白调节天然免疫的分子机制的研究。确定这种新的TRIM蛋白的细胞功能是了解它如何表现其抗病毒特性的先决条件。 公共卫生相关性：此前，我们鉴定了20种含有复杂抗病毒蛋白的TRIM E3连接酶蛋白。在这里，我们建议研究这些蛋白之一在先天免疫信号中的潜在作用。确定其细胞功能是了解其如何表现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.