Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration.
Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration.
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DOI：
10.1038/s41556-022-00997-7
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发表时间：
2022-10
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
在细胞迁移和极化过程中，许多信号转导和细胞骨架成分自组织产生局部突起。尽管生化和遗传分析已经描述了许多特定的相互作用，但如此多不同分子的激活和定位如何在亚细胞水平上进行时空协调仍不清楚。本研究表明，质膜内小叶表面负电荷的调控在分子相互作用中起着综合作用。表面电荷或zeta电位在新的突起处和Ras/PI3K/TORC2/F-actin网络激活的皮质波内短暂降低。内部小叶阴离子磷脂的快速改变，如PI(4,5)P2， PI(3,4)P2，磷脂酰丝氨酸和磷脂酸，共同促成了表面电荷的变化。通过招募带正电的光致动器突然减少表面电荷，足以触发整个生化网络，启动新生突起，并消除原有的极性。这些作用被Akt和PI3K/TORC2等关键信号成分的遗传或药理学抑制所阻断。相反，增加负表面电荷使网络失活，局部抑制化学引诱剂诱导的突起或破坏egf诱导的ERK激活。涉及可兴奋生化网络的计算模拟表明，由带电致动器的招募引起的反馈回路的微小变化可能导致对系统激活的巨大影响。我们提出关键的信号网络成分作用于表面电荷，并反过来被表面电荷作用，闭合反馈回路，从而带来自发突起形成、细胞迁移和极性建立所需的全球范围的分子自组织。
During cell migration and polarization, numerous signal transduction and cytoskeletal components self-organize to generate localized protrusions. Although biochemical and genetic analyses have delineated many specific interactions, how the activation and localization of so many different molecules are spatiotemporally orchestrated at the subcellular level has remained unclear. Here we show that the regulation of negative surface charge on the inner leaflet of the plasma membrane plays an integrative role in the molecular interactions. Surface charge, or zeta potential, is transiently lowered at new protrusions and within cortical waves of Ras/PI3K/TORC2/F-actin network activation. Rapid alterations of inner leaflet anionic phospholipids, such as PI(4,5)P2, PI(3,4)P2, phosphatidylserine, and phosphatidic acid, collectively contribute to the surface charge changes. Abruptly reducing the surface charge by recruiting positively charged optogenetic actuators was sufficient to trigger the entire biochemical network, initiate de novo protrusions, and abrogate pre-existing polarity. These effects were blocked by genetic or pharmacological inhibitions of key signaling components such as Akt and PI3K/TORC2. Conversely, increasing the negative surface charge deactivated the network and locally suppressed chemoattractant-induced protrusions or subverted EGF-induced ERK activation. Computational simulations involving excitable biochemical networks demonstrated that slight changes in feedback loops, induced by recruitment of the charged actuators, could lead to outsized effects on system activation. We propose that key signaling network components act on, and are in turn acted upon, by surface charge, closing feedback loops which bring about the global-scale molecular self-organization required for spontaneous protrusion formation, cell migration, and polarity establishment.
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影响因子：
21.3
作者：
Fort L;Batista JM;Thomason PA;Spence HJ;Whitelaw JA;Tweedy L;Greaves J;Martin KJ;Anderson KI;Brown P;Lilla S;Neilson MP;Tafelmeyer P;Zanivan S;Ismail S;Bryant DM;Tomkinson NCO;Chamberlain LH;Mastick GS;Insall RH;Machesky LM
通讯作者：
Machesky LM
影响因子：
13.6
作者：
Bhattacharya, Sayak;Banerjee, Tatsat;Iglesias, Pablo A.
通讯作者：
Iglesias, Pablo A.
影响因子：
64.8
作者：
Dang, Irene;Gorelik, Roman;Gautreau, Alexis
通讯作者：
Gautreau, Alexis
DOI：
10.1007/978-1-61779-166-6_26
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Cai, Huaqing;Huang, Chuan-Hsiang;Devreotes, Peter N;Iijima, Miho
通讯作者：
Iijima, Miho
DOI：
10.1146/annurev-cellbio-100616-060739
发表时间：
2017-10-06
影响因子：
11.3
作者：
Devreotes PN;Bhattacharya S;Edwards M;Iglesias PA;Lampert T;Miao Y
通讯作者：
Miao Y