Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway.

NF-kappa B signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-kappa B signaling is activated by a small subset of TNF family receptors and characterized by NF-kappa B2/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-kappa B signaling is sparse. Here we report a detailed state-of-the-art mass spectrometry-based protein protein interaction network including the non canonical NF-kappa B signaling nodes TRAF2, TRAF3, IKK alpha, NIK, and NF-kappa B2/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 IKK alpha interactor FKBP8, which may regulate processes downstream of noncanonical NF-kappa B signaling. To understand perturbed noncanonical NF-kappa B 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-kappa B signaling.