液-液相分离在细胞信号调控过程中的作用机制

Mechanisms of Liquid-liquid Phase Separation in Cell Signaling

近年来,液-液相分离(简称相分离)因其独特的功能与组织性,在细胞生物学研究中发展迅速。细胞内部分蛋白质及核酸(多为RNA)等生物大分子通过由多种弱多价相互作用及构象熵共同介导的相变(phase transition)形成无膜细胞器(membraneless organelles, MLOs)。这些无膜结构具有明显的流体性质,包括其圆形外表、可浸润、滴落和彼此融合,并具有动态的内部成分交换。在体内形成的无膜细胞器,广泛参与到包括细胞膜信号传导、膜结合蛋白质组装、染色质重塑、RNA代谢、突触传递、活跃转录中心形成、有丝分裂结构形成,以及蛋白质病理性转变等多种重要的细胞内信号调控过程。本文从相分离的研究背景,相分离发生的分子机制,正常相分离过程参与的多种细胞生理活动,异常相分离与神经性疾病及癌症发生的关系等方面,阐述了生物大分子的相分离在细胞信号调控过程中的普遍性及重要作用,并对研究相分离的实验技术和常用的相分离数据库进行了介绍。生物大分子相分离行为的发现,为重新理解众多结构及细胞生物学现象提供了全新的角度,生物大分子相分离可能作为一种新的生物学过程,帮助重新认识众多信号通路的调控方式,也有望为相关疾病的治疗提供新的方向。

In recent years,liquid-liquid phase separation(LLPS)has been rapidly developed in cell biology because of its unique function and organization.Proteins and nucleic acids(mostly RNA)in cells form membraneless organelles(MLOs)through phase transition mediated by various weak multivalent interactions and conformational entropy.These membraneless structures have distinct fluid properties,including the circular appearance,which can infiltrate,drip,fuse with each other,and have a dynamic exchange of internal components.The MLOs formed in vivo are widely involved in many important intracellular signaling processes,including cell membrane signaling,membrane binding protein assembly,chromatin remodeling,RNA metabolism,synaptic transmission,active transcription center formation,mitotic structure formation and pathological transformation of proteins.This review introduces the universality and importance of phase separation in signal regulation from the following aspects,including its discovery,molecular mechanism,the physiological activities involved in cells as well as the relationship between abnormal phase separation and neurological diseases or cancer.We also describe the experimental methods and databases related to phase separation.The discovery of LLPS of biological macromolecules provides a new perspective for us to understand many structural and cellular biological phenomena.As a new biological process,the phase separation of biomolecules may help us re-understand the regulation of many signaling pathways and hopefully provide a new direction for the treatment of related diseases.