<br>NIK-SIX 信号轴通过靶向沉默非经典 NF-κB 来控制炎症,Nature

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NIK-SIX 信号轴通过靶向沉默非经典 NF-κB 来控制炎症
Nature ( IF 50.5 ) Pub Date : 2019-03-20 , DOI: 10.1038/s41586-019-1041-6
Zixu Liu ₁ , Katrina B Mar ₁ , Natasha W Hanners ₂ , Sofya S Perelman ₁ , Mohammed Kanchwala ₃ , Chao Xing _{3,

4,

5} , John W Schoggins ₁ , Neal M Alto ₁

Affiliation

非经典 NF-κB 信号级联对于哺乳动物的淋巴器官发生、B 细胞成熟、破骨细胞分化和炎症至关重要 1,2；该系统的功能障碍与人类疾病有关，包括免疫紊乱和癌症3-6。尽管 NF-κB 诱导激酶（NIK，也称为 MAP3K14）的表达是非经典 NF-κB 通路激活的限速步骤2,7，但转录反应的调节机制仍然很大程度上未知。在这里，我们表明正弦眼同源盒 (SIX) 同源家族转录因子 SIX1 和 SIX2 是非规范 NF-κB 信号级联的组成部分。通过 NIK 介导的泛素蛋白酶体途径抑制，发育沉默的 6 种蛋白在分化的巨噬细胞中重新激活。因此，SIX1和SIX2靶向炎症基因启动子的子集，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，人类 SIX1 转基因抑制炎症并促进小鼠从内毒素休克中恢复。此外，SIX1和SIX2保护RAS/P53驱动的非小细胞肺癌免受SMAC模拟化疗药物（非经典NF-κB通路的小分子激活剂）诱导的炎症细胞死亡。我们的研究结果确定了 NIK-SIX 信号轴，可在生理和病理条件下微调炎症基因表达程序。非典型 NF-κB 受负反馈环路调节，该负反馈环路涉及 NIK 介导的 SIX1 和 SIX2 激活。

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A NIK–SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB

The non-canonical NF-κB signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals1,2; dysfunction of this system is associated with human diseases, including immunological disorders and cancer3–6. Although expression of NF-κB-inducing kinase (NIK, also known as MAP3K14) is the rate-limiting step in non-canonical NF-κB pathway activation2,7, 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-κB 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-κB pathway). Our findings identify a NIK–SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions.Non-canonical NF-κB is regulated by a negative feedback loop involving NIK-mediated activation of SIX1 and SIX2.

更新日期：2019-03-20

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