title: Expanding the Interactome of the Noncanonical NF-κB Signaling Pathway.
abstract: 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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Willmann
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Rui
authors.initials: R
authors.lastname: Martins
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Garncarz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Krolo
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.|Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases and CeRUD Vienna Center for Rare and Undiagnosed Diseases, 1090 Vienna, Austria.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
mesh_terms: D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D013058:Mass Spectrometry; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins; D000097782:NF-kappaB-Inducing Kinase; C471205:FKBP8 protein, human; C496559:CHUK protein, human
keywords: NF-κB inducing kinase; noncanonical NF-κB signaling; protein−protein interaction network; tandem affinity purification