title: Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation.
abstract: The NF-κB transcription factor mediates the inflammatory response through distinct (canonical and non-canonical) signaling pathways. The mechanisms controlling utilization of either of these pathways are largely unknown. Here we observe that TNF stimulation induces delayed NF-κB2/p100 processing and investigate the coupling mechanism. TNF stimulation induces TNF-associated factor-1 (TRAF-1) that directly binds NF-κB-inducing kinase (NIK) and stabilizes it from degradation by disrupting its interaction with TRAF2·cIAP2 ubiquitin ligase complex. We show that TRAF1 depletion prevents TNF-induced NIK stabilization and reduces p52 production. To further examine the interactions of TRAF1 and NIK with NF-κB2/p100 processing, we mathematically modeled TRAF1·NIK as a coupling signaling complex and validated computational inference by siRNA knockdown to show non-canonical pathway activation is dependent not only on TRAF1 induction but also NIK stabilization by forming TRAF1·NIK complex. Thus, these integrated computational-experimental studies of TNF-induced TRAF1 expression identified TRAF1·NIK as a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex. This feed-forward kinase pathway is essential for the activation of non-canonical pathway.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555. Electronic address: sachoudh@utmb.edu.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Choudhary
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Mridul
authors.initials: M
authors.lastname: Kalita
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Ling
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Kershaw V
authors.initials: KV
authors.lastname: Patel
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Chukwudi B
authors.initials: CB
authors.lastname: Edeh
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
mesh_terms: D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D008962:Models, Theoretical; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D047990:TNF Receptor-Associated Factor 1; D000097782:NF-kappaB-Inducing Kinase; C498206:NFKB2 protein, human
keywords: Inflammation; Mathematical Modeling; NF-κB Transcription Factor; NIK; TRAF; Tumor Necrosis Factor (TNF)
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