Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Nat Immunol. 2011 Oct 30;12(12):1167-75. doi: 10.1038/ni.2137.
Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.
Toll 样受体 (TLR) 信号激活转录因子 NF-κB (NF-κB) 抑制剂激酶 (IKK) 复合物，该复合物在炎症期间控制 NF-κB 介导的转录。核糖核酸酶 Regnase-1 通过控制编码细胞因子的 mRNA 的稳定性，在防止自身免疫中起着关键作用。在这里，我们表明 IKK 复合物通过响应 IL-1 受体 (IL-1R) 或 TLR 的刺激，通过磷酸化 Regnase-1 来控制白细胞介素 6 (IL-6) mRNA 的稳定性。磷酸化的 Regnase-1 发生泛素化和降解。Regnase-1 在 IL-1R 或 TLR 激活细胞中的表达降低一段时间后重新表达。Regnase-1 mRNA 可通过自身存在的茎环区域在 Regnase-1 3'非翻译区进行负调控。我们的数据表明，IKK 复合物不仅磷酸化 IκBα，从而激活转录，还磷酸化 Regnase-1，从而释放对 IL-6 mRNA 表达的“制动”。
