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.