Cell：加州大学科学家发现第四个IκB蛋白

生物谷

加州大学圣地亚哥分校(University of California-San Diego，简称UCSD)的研究人员发现了第四个IkB蛋白，在NF-kB的讯息传递路径上扮演着重要的角色。这项发现也多提供了一个治疗癌症的新方法，研究结果发表于1月26日的Cell期刊。

NF-κB是发炎反应过程中极为重要的分子，当细胞接受到来自细胞外的讯息刺激时，在细胞质中的NF-κB会由原先受IκB抑制的状态下解离出来，并呈现活化状态。活化之后的NF-κB进入细胞核中并引发特定基因转录及表现，产生后续发炎反应进一步导致肿瘤之发生。Alexander Hoffmann助理教授表示：先前已发现三个典型的(canonical) IκB蛋白能抑制NF-κB的活性，分别为IκBα、IκBb以及IκBe，而此研究则证实nfkb2/p100为第四个能抑制NF-κB的非典型(noncanonical)蛋白，p100分成两个抑制区块，其中一个区块能影响NF-κB的活性。

此研究发展出一套数学模式来观察NF-κB与p100之间的讯息模块，以观察NF-κB是否被活化而启动一连串的发炎反应，结合了计算机程序运算及实验研究数据，显示在突变的细胞中，也就是改变了典型或非典型IκB蛋白的平衡后，都会有不适当的发炎反应基因的表现，显示p100的确在NF-κB的讯息传递路径上具有抑制NF-κB活性的能力，这项发现对于生理学及病理学研究都相当重要。

(资料来源 : Bio.com)

英文原文摘要：

A Fourth IκB Protein within the NF-κB Signaling Module

Soumen Basak1, 2, Hana Kim1, 2, Jeffrey D. Kearns1, 2, Vinay Tergaonkar3, 5, Ellen O'Dea1, 2, Shannon L. Werner1, 2, Chris A. Benedict4, Carl F. Ware4, Gourisankar Ghosh1, Inder M. Verma3 and Alexander Hoffmann1, 2, ,

1Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
2Signaling Systems Laboratory, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
3Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
4La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA

Summary

Inflammatory NF-κB/RelA activation is mediated by the three canonical inhibitors, IκBα, -β, and - var epsilon . We report here the characterization of a fourth inhibitor, nfκb2/p100, that forms two distinct inhibitory complexes with RelA, one of which mediates developmental NF-κB activation. Our genetic evidence confirms that p100 is required and sufficient as a fourth IκB protein for noncanonical NF-κB signaling downstream of NIK and IKK1. We develop a mathematical model of the four-IκB-containing NF-κB signaling module to account for NF-κB/RelA:p50 activation in response to inflammatory and developmental stimuli and find signaling crosstalk between them that determines gene-expression programs. Further combined computational and experimental studies reveal that mutant cells with altered balances between canonical and noncanonical IκB proteins may exhibit inappropriate inflammatory gene expression in response to developmental signals. Our results have important implications for physiological and pathological scenarios in which inflammatory and developmental signals converge.