title: SMN1 functions as a novel inhibitor for TRAF6-mediated NF-κB signaling.
abstract: Survival motor neuron (SMN) is a 38-kDa protein, whose deficiency in humans develops spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disease with muscular atrophy due to motor neuron death in the spinal cord. We now report that SMN prevents the activation of TRAF6 and IκB kinase (IKK) and thereby negatively regulates the NF-κB signaling processes. SMN physically interacted with TRAF6 and with each component of the IKK complex, IKK-α, IKK-β, and IKK-γ in BV2 microglia cells. Moreover, SMN1 inhibited the E3 ubiquitin ligase activity of TRAF6 as well as the kinase activity of IKK. Furthermore, depletion of endogenous SMN by RNA interference enhanced the IL-1β-induced activation of IKK and production of inflammatory mediators such as TNF-α and nitric oxide in BV2 cells. Consistently, the potentiation of IL-1β-induced IKK activity was also found in SMA patient fibroblasts, compared with that of normal ones. Our results thus suggest that SMN functions as a natural inhibitor for IL-1β-induced NF-κB signaling by targeting TRAF6 and the IKK complex.
authors.affiliation: Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea. Electronic address: ejchoi@korea.ac.kr.
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D048029:TNF Receptor-Associated Factor 6; D051550:I-kappa B Kinase
keywords: NF-κB signaling; Spinal muscular atrophy; Survival motor neuron; TRAF6