Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China; and.
Department of Pathogen Biology and Immunology, School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, People's Republic of China
J Immunol. 2020 Jun 1;204(11):3008-3018. doi: 10.4049/jimmunol.1901042. Epub 2020 Apr 17.
Proper regulation of innate immune response is important for individual health. The NF-κB signaling pathway plays crucial roles in innate immunity and inflammation, and its aberrant activation is implicated in diverse diseases and disorders. In this study, we report that calmodulin-like 6 (CALML6), a member of the EF-hand protein family, is a negative regulator of the NF-κB signaling pathway. CALML6 attenuated TNF-stimulated phosphorylation of proteins downstream of TGF-β-activated kinase 1 (TAK1) and inhibited TAK1-induced NF-κB activation. Further studies showed that CALML6 interacted with TAK1 and recruited the deubiquitylating enzyme cylindromatosis to repress the K63-linked polyubiquitination of TAK1. CALML6 transgenic mice had higher tolerances to lethal LPS treatment in vivo. These findings suggest that CALML6 is a negative regulator of the NF-κB signaling pathway, which is important for maintaining the balance of the innate immune response.
适当调节先天免疫反应对于个体健康非常重要。NF-κB 信号通路在先天免疫和炎症中发挥关键作用，其异常激活与多种疾病和失调有关。在这项研究中，我们报告钙调蛋白样蛋白 6（CALML6）是 EF 手蛋白家族的成员，是 NF-κB 信号通路的负调控因子。CALML6 减弱了 TNF 刺激的 TGF-β激活激酶 1（TAK1）下游蛋白的磷酸化，并抑制了 TAK1 诱导的 NF-κB 激活。进一步的研究表明，CALML6 与 TAK1 相互作用，并招募去泛素化酶 cylindromatosis 来抑制 TAK1 的 K63 连接多泛素化。CALML6 转基因小鼠在体内对致死性 LPS 处理有更高的耐受性。这些发现表明，CALML6 是 NF-κB 信号通路的负调控因子，对于维持先天免疫反应的平衡非常重要。
