Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity
Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity
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DOI：
10.1073/pnas.1000093107
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发表时间：
2011-03-15
影响因子：
11.1
通讯作者：
Xavier, Ramnik J.
中科院分区：
文献类型：
--
作者：
Ng, Aylwin C. Y.;Eisenberg, Jason M.;Xavier, Ramnik J.
在先天免疫传感中，通过识别受体检测病原体相关的分子模式通常涉及富含亮氨酸的重复序列（LRR）。我们提供了一个375人LRR含蛋白质的分类，其中几乎一半缺乏其他可识别的功能结构域。我们首先将LRR分配到LRR类，然后根据这些类分配对蛋白质进行分组，从而对人类LRR蛋白进行聚类，揭示了几个包含大量具有某些非LRR功能结构域的蛋白质的所得蛋白质组。特别地，在典型（T）和细菌+典型（S+T）类别中的统计学显著数量的LRR蛋白具有跨膜结构域，而在含半胱氨酸（CC）类别中的大多数LRR蛋白含有F-box结构域（其介导与E3泛素连接酶复合物的相互作用）。此外，通过研究的LRR蛋白的进化概况，我们确定了一个子集的LRR蛋白表现出强烈的保护真菌和富集的“核酸结合”功能。LRR基因的表达分析鉴定了感染病原菌的人原代巨噬细胞中病原体应答基因的子集。使用功能性RNAi，我们表明MFHAS 1调节Toll样受体（TLR）依赖性信号传导。通过使用蛋白质相互作用网络分析，然后进行功能性RNAi，我们将LRSAM 1鉴定为抗菌自噬反应的组成部分。
In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant-number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response.