Contact-dependent incorporation of endoplasmic reticulum into retraction fibers and migrasomes

Migrating cells form retraction fibers (RFs) at their trailing edge, where migrasomes, ranging from 0.5 to 3 μm, grow at the tips or intersections of RF. Migrasomes play crucial roles when released extracellularly, but before release, they remain physically connected to cell body via RFs, facilitating long-range signal transmission. Since many signaling molecules are highly localized, the mechanism of long-range signal transmission has not been fully understood. Here, we demonstrated that tubular ER extended into RFs and localized to migrasomes, which depended on microtubule-regulated ER extension. Tubular ER adhered to migrasome biogenesis site through ER-plasma membrane contact sites (ER–PM MCSs). Notably, tubular ER functions as cholesterol and calcium reservoir, facilitating the transfer of cholesterol and calcium to migrasomes, potentially at ER–PM MCSs that promoted membrane expansion, stability, and localized secretion of migrasome. Our findings revealed a novel dynamic of tubular ER and provided a new mechanism for long-range site-specific calcium and cholesterol transmission through RFs and migrasomes in migrating cells.