2021年10月21日，美国哈佛大学吴皓、中国科学与技术大学朱书等研究人员合作在《细胞》杂志发表论文，揭示相分离驱动RNA病毒诱导的NLRP6炎性体激活。
研究人员表明NLRP6在体外和细胞内与双链RNA（dsRNA）相互作用时发生液-液相分离（LLPS），NLRP6的一个本质上无序的多赖氨酸序列（K350-354）对多价相互作用、相分离和炎性体的激活非常重要。Nlrp6缺陷或Nlrp6K350-354A突变体小鼠在小鼠肝炎病毒或轮状病毒感染时，以及在肠道微生物群刺激下的稳定状态下，显示出炎性体激活的减少，这意味着NLRP6 LLPS在抗微生物免疫方面的作用。
通过螺旋装配招募的ASC能巩固NLRP6凝结物，ASC进一步招募并激活caspase-1。Lipotehoic acid，一种已知的NLRP6配体，也能促进NLRP6 LLPS；DHX15，一种NLRP6诱导的干扰素信号螺旋酶，与NLRP6和dsRNA共同形成凝集物。因此，NLRP6的LLPS是对配体刺激的一种共同反应，其作用是根据细胞环境将NLRP6导向不同的功能结果。
据介绍，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，在宿主防御中非常重要。
附：英文原文
Title: Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome
Author: Chen Shen, Runzhi Li, Roberto Negro, Jiewei Cheng, Setu M. Vora, Tian-Min Fu, Anmin Wang, Kaixin He, Liudmila Andreeva, Pu Gao, Zhigang Tian, Richard A. Flavell, Shu Zhu, Hao Wu
Issue&Volume: 2021-10-21
Abstract: NLRP6 is important in host defense by inducing functional outcomes including inflammasomeactivation and interferon production. Here, we show that NLRP6 undergoes liquid-liquidphase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) ofNLRP6 is important for multivalent interactions, phase separation, and inflammasomeactivation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirusinfection, and in steady state stimulated by intestinal microbiota, implicating NLRP6LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifiesNLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoicacid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-inducedinterferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6is a common response to ligand stimulation, which serves to direct NLRP6 to distinctfunctional outcomes depending on the cellular context.
DOI: 10.1016/j.cell.2021.09.032
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01115-6