小柯机器人

DDX3X蛋白调控细胞生死抉择
2019-09-12 15:49
美国圣犹达儿童研究医院Thirumala-Devi Kanneganti和英国李嘉诚中心癌症研究所Richard J. Gilbertson等研究人员合作,发现DDX3X蛋白通过调节NLRP3炎症小体,在应激细胞中起着决定生死的检查点作用。相关论文2019年9月11日在线发表在《自然》上。

研究人员发现应激颗粒的产生特异性抑制NLRP3炎性小体激活、ASC斑点形成和细胞焦亡。应激颗粒蛋白DDX3X与NLRP3相互作用以驱动炎性小体激活。应激颗粒的组装导致DDX3X的隔离,从而抑制NLRP3炎性小体激活。应激颗粒和NLRP3炎性小体竞争DDX3X分子以协调在应激条件下先天反应的激活和随后的细胞命运决定。骨髓室中应激颗粒的诱导或DDX3X的缺失导致体内炎性小体依赖性细胞因子的产生减少。这些研究结果表明,巨噬细胞利用DDX3X的可用性来解析应激信号,并在促生存应激颗粒和焦痂ASC斑点之间进行选择。总之,这些数据证明了DDX3X在驱动NLRP3炎性体和应力颗粒装配中的作用,并提出了一种类似变阻器的机制模式,从而用于调节压力条件下细胞生死的命运决定。

据悉,细胞应激反应通过调节细胞存活和死亡在调节体内平衡中起重要作用。应激颗粒是细胞质的区室,使细胞能够在各种压力下存活。应激颗粒的组装和拆卸缺陷与神经退行性疾病、异常抗病毒反应以及癌症有关。炎性小体是多蛋白质异聚体复合物,其感知与损伤或细胞内病原体相关的分子模式,并组装成称为ASC斑点的细胞质区室,以促进caspase-1的活化。炎性小体的激活诱导白细胞介素(IL)-1β和IL-18的分泌,并促使细胞命运走向焦亡,这是一种程序性炎症细胞死亡形式,在健康和疾病中起主要作用。虽然应激颗粒和炎性小体都可以通过感知细胞应激来触发,但它们驱使了相反的细胞命运决定。应激颗粒和炎性小体之间的交流及其如何影响细胞命运尚未得到很好的研究。

附:英文原文

Title:DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome

Author:Parimal Samir, Sannula Kesavardhana, Deanna M. Patmore, Sebastien Gingras, R. K. Subbarao Malireddi, Rajendra Karki, Clifford S. Guy, Benoit Briard, David E. Place, Anannya Bhattacharya, Bhesh Raj Sharma, Amanda Nourse, Sharon V. King, Aaron Pitre, Amanda R. Burton, Stephane Pelletier, Richard J. Gilbertson, Thirumala-Devi Kanneganti 

Issue&Volume: 2019-09-11

Abstract:

The cellular stress response has a vital role in regulating homeostasis by modulating cell survival and death. Stress granules are cytoplasmic compartments that enable cells to survive various stressors. Defects in the assembly and disassembly of stress granules are linked to neurodegenerative diseases, aberrant antiviral responses and cancer1,2,3,4,5. Inflammasomes are multi-protein heteromeric complexes that sense molecular patterns that are associated with damage or intracellular pathogens, and assemble into cytosolic compartments known as ASC specks to facilitate the activation of caspase-1. Activation of inflammasomes induces the secretion of interleukin (IL)-1β and IL-18 and drives cell fate towards pyroptosis—a form of programmed inflammatory cell death that has major roles in health and disease6,7,8,9,10,11,12. Although both stress granules and inflammasomes can be triggered by the sensing of cellular stress, they drive contrasting cell-fate decisions. The crosstalk between stress granules and inflammasomes and how this informs cell fate has not been well-studied. Here we show that the induction of stress granules specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The stress granule protein DDX3X interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages use the availability of DDX3X to interpret stress signals and choose between pro-survival stress granules and pyroptotic ASC specks. Together, our data demonstrate the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggest a rheostat-like mechanistic paradigm for regulating live-or-die cell-fate decisions under stress conditions.

DOI:10.1038/s41586-019-1551-2

Source:https://www.nature.com/articles/s41586-019-1551-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0