Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway

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.