The migrasome is an organelle of migrating cells with diverse physiological functions. How migrasome formation is initiated is unknown. We found that sphingomyelin is enriched in migrasomes and identified sphingomyelin synthase 2 (SMS2) as an essential protein for migrasome biogenesis. SMS2 assembles into immobile foci that adhere on the basal membrane at the leading edge. When cells migrate away, the SMS2 foci ‘move’ out of cells and into retraction fibres, where they become migrasome formation sites and eventually grow into migrasomes. Mechanistically, SMS2 foci seed migrasomes by converting ceramide to sphingomyelin, which is essential for migrasome formation. Furthermore, CerS5, which is required for the synthesis of long-chain ceramide, and CERT, which transports ceramide from the endoplasmic reticulum to Golgi, are both required for migrasome formation. Our data reveal the essential role of ceramide and sphingomyelin in migrasome formation and suggest that SMS2 forms basal membrane-surface-connecting structures that pre-determine where migrasomes will grow.

迁移体是具有多种生理功能的迁移细胞的细胞器。迁移体的形成是如何启动的尚不清楚。我们发现鞘磷脂在迁移小体中富集，并确定鞘磷脂合酶 2 (SMS2) 是迁移小体生物发生的必需蛋白质。SMS2 组装成固定的病灶，粘附在前缘的基底膜上。当细胞迁移离开时，SMS2 焦点“移”出细胞并进入回缩纤维，在那里它们成为迁移体形成位点并最终长成迁移体。从机制上讲，SMS2 foci 通过将神经酰胺转化为鞘磷脂来种子迁移小体，这对于迁移小体的形成至关重要。此外，合成长链神经酰胺所需的CerS5和将神经酰胺从内质网转运至高尔基体的CERT都是迁移体形成所必需的。我们的数据揭示了神经酰胺和鞘磷脂在迁移小体形成中的重要作用，并表明 SMS2 形成基底膜表面连接结构，预先决定迁移小体的生长位置。