Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea.
Nat Immunol. 2011 Jul 3;12(8):742-51. doi: 10.1038/ni.2064.
The orphan nuclear receptor SHP (small heterodimer partner) is a transcriptional corepressor that regulates hepatic metabolic pathways. Here we identified a role for SHP as an intrinsic negative regulator of Toll-like receptor (TLR)-triggered inflammatory responses. SHP-deficient mice were more susceptible to endotoxin-induced sepsis. SHP had dual regulatory functions in a canonical transcription factor NF-κB signaling pathway, acting as both a repressor of transactivation of the NF-κB subunit p65 and an inhibitor of polyubiquitination of the adaptor TRAF6. SHP-mediated inhibition of signaling via the TLR was mimicked by macrophage-stimulating protein (MSP), a strong inducer of SHP expression, via an AMP-activated protein kinase-dependent signaling pathway. Our data identify a previously unrecognized role for SHP in the regulation of TLR signaling.
孤儿核受体 SHP（小异二聚体伴侣）是一种转录共抑制因子，可调节肝脏代谢途径。在这里，我们确定了 SHP 作为 Toll 样受体 (TLR) 触发的炎症反应的内在负调节剂的作用。SHP 缺陷型小鼠对内毒素诱导的败血症更敏感。SHP 在经典转录因子 NF-κB 信号通路中具有双重调节功能，既作为 NF-κB 亚基 p65 的转录激活的抑制剂，又作为衔接蛋白 TRAF6 的多泛素化的抑制剂。通过 AMP 激活的蛋白激酶依赖的信号通路，巨噬细胞刺激蛋白 (MSP)（SHP 的强诱导剂）模拟了 SHP 通过 TLR 介导的信号抑制。我们的数据确定了 SHP 在调节 TLR 信号中的先前未被认识到的作用。
