Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains
Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains
复制标题
迁移体的形成是由微米级四跨膜蛋白宏结构域的组装介导的
DOI：
10.1038/s41556-019-0367-5
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发表时间：
2019-08-01
影响因子：
21.3
通讯作者：
Yu, Li
中科院分区：
文献类型：
--
作者：
Huang, Yuwei;Zucker, Ben;Yu, Li
迁移体是近期发现的细胞器，在迁移细胞的收缩纤维上形成大的囊泡样结构。虽然迁移体的形成过程之前已有描述，但迁移体生物发生的分子机制仍不清楚。在此，我们提出迁移体的形成机制包括将富含四跨膜蛋白和胆固醇的膜微区组装成微米级的宏区，这些宏区膨胀形成迁移体。该机制的主要发现是四跨膜蛋白和胆固醇对迁移体的形成是必要且充分的。我们通过活细胞实验证明了四跨膜蛋白和胆固醇的必要性，并通过在重组膜系统中产生类迁移体结构证明了它们的充分性。我们通过一个理论模型证实了该机制，该模型提出驱动迁移体形成的关键因素是富含四跨膜蛋白和胆固醇的宏区的膜刚度增加。最后，通过对四跨膜蛋白4和胆固醇的膜硬化效应的实验验证，对该理论模型进行了定量验证。
Migrasomes are recently discovered cellular organelles that form as large vesicle-like structures on retraction fibres of migrating cells. While the process of migrasome formation has been described before, the molecular mechanism underlying migrasome biogenesis remains unclear. Here, we propose that the mechanism of migrasome formation consists of the assembly of tetraspanin- and cholesterol-enriched membrane microdomains into micron-scale macrodomains, which swell into migrasomes. The major finding underlying the mechanism is that tetraspanins and cholesterol are necessary and sufficient for migrasome formation. We demonstrate the necessity of tetraspanins and cholesterol via live-cell experiments, and their sufficiency by generating migrasome-like structures in reconstituted membrane systems. We substantiate the mechanism by a theoretical model proposing that the key factor driving migrasome formation is the elevated membrane stiffness of the tetraspanin- and cholesterol-enriched macrodomains. Finally, the theoretical model was quantitatively validated by experimental demonstration of the membrane-stiffening effect of tetraspanin 4 and cholesterol.