Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway

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• 作者：Katharina L. Willmann ; Roberto Sacco ; Rui Martins ; Wojciech Garncarz ; Ana Krolo ; Sylvia Knapp ; Keiryn L. Bennett ; Kaan Boztug
• 刊名：Journal of Proteome Research
• 出版年：2016
• 出版时间：September 2, 2016
• 年：2016
• 卷：15
• 期：9
• 页码：2900-2909
• 全文大小：622K
• 年卷期：0
• ISSN：1535-3907

文摘

NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate noncanonical NF-κB signaling is sparse. Here we report a detailed state-of-the-art mass spectrometry-based protein–protein interaction network including the noncanonical NF-κB signaling nodes TRAF2, TRAF3, IKKα, NIK, and NF-κB2/p100. The value of the data set was confirmed by the identification of interactions already known to regulate this pathway. In addition, a remarkable number of novel interactors were identified. We provide validation of the novel NIK and IKKα interactor FKBP8, which may regulate processes downstream of noncanonical NF-κB signaling. To understand perturbed noncanonical NF-κB signaling in the context of misregulated NIK in disease, we also provide a differential interactome of NIK mutants that cause immunodeficiency. Altogether, this data set not only provides critical insight into how protein–protein interactions can regulate immune signaling but also offers a novel resource on noncanonical NF-κB signaling.