Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Immunity. 2011 Jun 24;34(6):843-53. doi: 10.1016/j.immuni.2011.02.022.
Tight regulation of NF-κB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here, we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF-κB activation. NLRX1 interacts with TRAF6 or IκB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6, and then binds to the IKK complex, resulting in inhibition of IKKα and IKKβ phosphorylation and NF-κB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-κB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-κB activation by dynamically interacting with TRAF6 and the IKK complex.
NF-κB 信号的紧密调节对于先天和适应性免疫反应至关重要，但负责其负调节的分子机制尚不完全清楚。在这里，我们报告 NLRX1，一种 NOD 样受体家族成员，负调节 Toll 样受体介导的 NF-κB 激活。NLRX1 以激活信号依赖性的方式与 TRAF6 或 IKK 激酶（IKK）相互作用。在 LPS 刺激下，NLRX1 迅速被泛素化，与 TRAF6 解离，然后与 IKK 复合物结合，导致 IKKα 和 IKKβ 磷酸化和 NF-κB 激活的抑制。在各种细胞类型中敲低 NLRX1 后，LPS 刺激后 IKK 磷酸化和 NF-κB 反应性细胞因子的产生明显增强。我们进一步提供体内证据表明，在小鼠中敲低 NLRX1 可显著增强 LPS 诱导的败血症休克和血浆 IL-6 水平的易感性。我们的研究确定了 NLRX1 在动态与 TRAF6 和 IKK 复合物相互作用的 TLR 诱导的 NF-κB 激活的负调节中的先前未被认识的作用。
