Mansell Ashley, Smith Rosealee, Doyle Sarah L, Gray Pearl, Fenner Jennifer E, Crack Peter J, Nicholson Sandra E, Hilton Douglas J, O'Neill Luke A J, Hertzog Paul J
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia.
Nat Immunol. 2006 Feb;7(2):148-55. doi: 10.1038/ni1299. Epub 2006 Jan 15.
Toll-like receptor (TLR) signals that initiate innate immune responses to pathogens must be tightly regulated to prevent excessive inflammatory damage to the host. The adaptor protein Mal is specifically involved in signaling via TLR2 and TLR4. We demonstrate here that after TLR2 and TLR4 stimulation Mal becomes phosphorylated by Bruton's tyrosine kinase (Btk) and then interacts with SOCS-1, which results in Mal polyubiquitination and subsequent degradation. Removal of SOCS-1 regulation potentiates Mal-dependent p65 phosphorylation and transactivation of NF-kappaB, leading to amplified inflammatory responses. These data identify a target of SOCS-1 that regulates TLR signaling via a mechanism distinct from an autocrine cytokine response. The transient activation of Mal and subsequent SOCS-1-mediated degradation is a rapid and selective means of limiting primary innate immune response.
启动对病原体的固有免疫反应的Toll样受体（TLR）信号必须受到严格调控，以防止对宿主造成过度的炎症损伤。衔接蛋白Mal特别参与通过TLR2和TLR4的信号传导。我们在此证明，在TLR2和TLR4刺激后，Mal被布鲁顿酪氨酸激酶（Btk）磷酸化，然后与SOCS-1相互作用，这导致Mal多聚泛素化并随后降解。去除SOCS-1的调控会增强Mal依赖的p65磷酸化和NF-κB的反式激活，导致炎症反应放大。这些数据确定了SOCS-1的一个靶点，该靶点通过一种不同于自分泌细胞因子反应的机制调节TLR信号传导。Mal的短暂激活以及随后SOCS-1介导的降解是限制原发性固有免疫反应的一种快速且选择性的方式。
