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Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome
Cell ( IF 64.5 ) Pub Date : 2021-10-21 , DOI: 10.1016/j.cell.2021.09.032
Chen Shen 1 , Runzhi Li 2 , Roberto Negro 3 , Jiewei Cheng 2 , Setu M Vora 1 , Tian-Min Fu 4 , Anmin Wang 2 , Kaixin He 2 , Liudmila Andreeva 1 , Pu Gao 5 , Zhigang Tian 2 , Richard A Flavell 6 , Shu Zhu 2 , Hao Wu 1
Affiliation  

NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.



中文翻译:

相分离驱动 RNA 病毒诱导的 NLRP6 炎性体激活

NLRP6 通过诱导包括炎性体激活和干扰素产生在内的功能结果在宿主防御中很重要。在这里,我们表明 NLRP6在体外和细胞内与双链 RNA (dsRNA) 相互作用时会发生液-液相分离 (LLPS) ,并且 NLRP6 的本质上无序的多聚赖氨酸序列 (K350-354) 对于多价相互作用、相分离和炎性小体激活。Nlrp6 缺陷Nlrp6 K350-354A突变小鼠在小鼠肝炎病毒或轮状病毒感染后显示炎症小体激活减少,并且在肠道微生物群刺激下处于稳定状态,表明 NLRP6 LLPS 与抗微生物免疫有关。通过螺旋组装募集 ASC 固化 NLRP6 凝聚物,ASC 进一步募集并激活 caspase-1。脂磷壁酸是一种已知的 NLRP6 配体,也促进 NLRP6 LLPS,而 DHX15 是 NLRP6 诱导的干扰素信号转导中的解旋酶,与 NLRP6 和 dsRNA 共形成缩合物。因此,NLRP6 的 LLPS 是对配体刺激的常见反应,它根据细胞环境将 NLRP6 引导至不同的功能结果。

更新日期:2021-11-11
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