ATP-dependent one-dimensional movement maintains immune homeostasis by suppressing spontaneous MDA5 filament assembly.

IF 25.9 1区 生物学 Q1 CELL BIOLOGY
Xiao-Peng Han,Ming Rao,Yu Chang,Jun-Yan Zhu,Jun Cheng,Yu-Ting Li,Wu Qiong,Si-Chao Ye,Qiurong Zhang,Shao-Qing Zhang,Ling-Ling Chen,Fajian Hou,Jin Zhong,Jiaquan Liu
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引用次数: 0

Abstract

MDA5 is a RIG-I-like receptor (RLR) that recognizes viral double-stranded RNA (dsRNA) to initiate the innate immune response. Its activation requires filament formation along the dsRNA, which triggers the oligomerization of N-terminal caspase activation and recruitment domains. The ATPase activity of MDA5 is critical for immune homeostasis, likely by regulating filament assembly. However, the molecular basis underlying this process remains poorly understood. Here, we show that MDA5 operates as an ATP-hydrolysis-driven motor that translocates along dsRNA in a one-dimensional (1D) manner. Multiple MDA5 motors can cooperatively load onto a single dsRNA, but their movements rarely synchronize, inhibiting spontaneous filament formation and activation. LGP2, a key regulator of MDA5 signaling, recognizes MDA5 motors and blocks their movement, thereby promoting filament assembly through a translocation-directed mechanism. This unique assembly strategy underscores the role of 1D motion in higher-order protein oligomerization and reveals a novel mechanism for maintaining immune homeostasis.
atp依赖的一维运动通过抑制自发的MDA5丝组装来维持免疫稳态。
MDA5是一种rig - i样受体(RLR),可识别病毒双链RNA (dsRNA)启动先天免疫反应。它的激活需要沿着dsRNA形成丝,这触发n端caspase激活和募集结构域的寡聚化。MDA5的atp酶活性对免疫稳态至关重要,可能通过调节丝的组装。然而,这一过程背后的分子基础仍然知之甚少。在这里,我们发现MDA5作为atp水解驱动的马达,沿着dsRNA以一维(1D)方式易位。多个MDA5马达可以协同加载到单个dsRNA上,但它们的运动很少同步,抑制了自发细丝的形成和激活。LGP2是MDA5信号的关键调控因子,它识别MDA5马达并阻断其运动,从而通过易位导向机制促进丝的组装。这种独特的组装策略强调了一维运动在高阶蛋白质寡聚化中的作用,并揭示了维持免疫稳态的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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