A novel TRIM protein involved in innate immunity

描述（由申请人提供）：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E3连接酶TRIM家族的极大兴趣，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在干扰素的作用下被上调，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，我们鉴定出约20种TRIM蛋白具有复杂的抗病毒活性（Uchil et al., 2008）。我们假设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。TRIM25等蛋白的表达触发先天免疫信号级联反应，导致抗病毒状态的建立。为了鉴定与先天免疫相似的新型TRIM蛋白，我们筛选了所有55种蛋白，以确定它们激活或负调节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的一些额外的阳性调节因子。在这里，我们建议研究其中一种似乎在toll样受体（TLR）信号传导中起重要作用的蛋白质。具体来说，我们将测试其在TLR4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.