A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB
A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB
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DOI：
10.1038/s41586-019-1041-6
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发表时间：
2019-04-11
期刊：
影响因子：
64.8
通讯作者：
Alto, Neal M.
中科院分区：
文献类型：
--
作者：
Liu, Zixu;Mar, Katrina B.;Alto, Neal M.
非经典NF-κ B信号级联对于哺乳动物中的淋巴器官形成、B细胞成熟、破骨细胞分化和炎症是必需的（1，2）;该系统的功能障碍与人类疾病相关，包括免疫性疾病和癌症（3-6）。尽管NF-κ B诱导激酶（NIK，也称为MAP 3 K14）的表达是非经典NF-κ B途径活化的限速步骤（2，7），但调节转录应答的机制在很大程度上仍不清楚。在这里，我们表明，正弦眼同源框（SIX）同源家族转录因子SIX 1和SIX 2的非经典NF-κ B信号级联的组成部分。发育沉默的SIX蛋白在分化的巨噬细胞中通过NIK介导的泛素蛋白酶体途径的抑制被重新激活。因此，SIX 1和SIX 2靶向炎性基因启动子的子集，并直接抑制负反馈回路中转录因子RELA和RELB的反式激活功能。为了支持SIX蛋白在宿主免疫中的生理学关键作用，人SIX 1转基因抑制炎症并促进小鼠从内毒素休克中恢复。此外，SIX 1和SIX 2保护RAS/P53驱动的非小细胞肺癌免受SMAC模拟化疗剂（非经典NF-κ B途径的小分子激活剂）诱导的炎性细胞死亡。我们的研究结果确定了一个NIK-SIX信号传导轴，该轴在生理和病理条件下微调炎症基因表达程序。
The non-canonical NF-kappa B signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals(1,2); dysfunction of this system is associated with human diseases, including immunological disorders and cancer(3-6). Although expression of NF-kappa B-inducing kinase (NIK, also known as MAP3K14) is the rate-limiting step in non-canonical NF-kappa B pathway activation(2,7), the mechanisms by which transcriptional responses are regulated remain largely unknown. Here we show that the sine oculis homeobox (SIX) homologue family transcription factors SIX1 and SIX2 are integral components of the non-canonical NF-kappa B signalling cascade. The developmentally silenced SIX proteins are reactivated in differentiated macrophages by NIK-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 target a subset of inflammatory gene promoters and directly inhibit the trans-activation function of the transcription factors RELA and RELB in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS/P53-driven non-small-cell lung carcinomas from inflammatory cell death induced by SMAC-mimetic chemotherapeutic agents (small-molecule activators of the non-canonical NF-kappa B pathway). Our findings identify a NIK-SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.