Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway

• Published in: Journal of proteome research 2016-09, Vol.15 (9), p.2900-2909
• Main Authors: Willmann, Katharina L, Sacco, Roberto, Martins, Rui, Garncarz, Wojciech, Krolo, Ana, Knapp, Sylvia, Bennett, Keiryn L, Boztug, Kaan
• Format: Article
• Language: English
• Subjects: Humans; I-kappa B Kinase - metabolism; Mass Spectrometry; Mutation; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; Protein Binding; Protein Interaction Maps; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Signal Transduction - immunology; Tacrolimus Binding Proteins - metabolism
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/acs.jproteome.5b01004

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.