title: A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS).
abstract: Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.
authors.affiliation: School of Life Sciences, The University of Nottingham, UK; Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Ola H
authors.initials: OH
authors.lastname: Negm
authors.forename: Heiko A
authors.initials: HA
authors.lastname: Mannsperger
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McDermott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Drewe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Powell
authors.forename: Ian
authors.initials: I
authors.lastname: Todd
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Fairclough
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Tighe
mesh_terms: D045744:Cell Line, Tumor; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D040081:Protein Array Analysis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Autoinflammation; Protein microarray; Signalome; TNF receptor 1; TRAPS