The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
Beijing Frontier Research Center for Biological Structure, Beijing, China.
Nat Cell Biol. 2019 Aug;21(8):991-1002. doi: 10.1038/s41556-019-0367-5. Epub 2019 Aug 1.
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.
迁移体是最近发现的细胞细胞器，在迁移细胞的回缩纤维上形成大的囊泡样结构。虽然迁移体的形成过程已经被描述过，但迁移体生物发生的分子机制仍不清楚。在这里，我们提出迁移体的形成机制包括富含四跨膜蛋白和胆固醇的膜微区组装成微米级的巨域，这些巨域膨胀成迁移体。该机制的主要发现是四跨膜蛋白和胆固醇是迁移体形成所必需和充分的。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，通过在重组膜系统中产生类似迁移体的结构证明了它们的充分性。我们通过一个理论模型来证实这个机制，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巨域的膜刚性增加。最后，通过实验证明四跨膜蛋白 4 和胆固醇的膜刚性增强效应，对理论模型进行了定量验证。
