Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea.
Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, South Korea.
Biochim Biophys Acta Mol Cell Res. 2017 May;1864(5):760-770. doi: 10.1016/j.bbamcr.2017.02.011. Epub 2017 Feb 16.
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.
运动神经元存活蛋白（SMN）是一种 38kDa 的蛋白质，其在人体中的缺乏会导致脊髓性肌萎缩症（SMA），这是一种常染色体隐性神经退行性疾病，由于脊髓运动神经元死亡导致肌肉萎缩。我们现在报告称，SMN 可防止 TRAF6 和 IκB 激酶（IKK）的激活，从而负调控 NF-κB 信号通路。SMN 在 BV2 小胶质细胞中与 TRAF6 以及 IKK 复合物的各个成分（IKK-α、IKK-β 和 IKK-γ）发生物理相互作用。此外，SMN1 抑制 TRAF6 的 E3 泛素连接酶活性以及 IKK 的激酶活性。此外，通过 RNA 干扰耗尽内源性 SMN 会增强 BV2 细胞中 IL-1β 诱导的 IKK 激活和炎性介质（如 TNF-α 和一氧化氮）的产生。一致地，与正常细胞相比，在 SMA 患者成纤维细胞中也发现了 IL-1β 诱导的 IKK 活性的增强。因此，我们的结果表明，SMN 通过靶向 TRAF6 和 IKK 复合物，作为一种天然抑制剂，发挥作用，抑制 IL-1β 诱导的 NF-κB 信号通路。
