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How Migrasomes Form

How do migrasomes form?

Migrasome formation is a series of complex and tightly controlled biological and membrane-mechanical processes.

Conceptual formation model showing a substrate-anchored SMS2-like focus entering a retraction fiber, coordinated precursor maturation and TSPAN/TEM-rich migrasome expansion.

Formation Mechanisms

Mechanistic analysis of migrasome formation

  1. Conceptual close view of a basal cell membrane attached to extracellular matrix through multiple integrin-like contacts, with a coral membrane swelling continuous with intersecting retraction fibres.

    Formation site

    Migrasomes enlarge on retraction fibres left behind by a migrating cell rather than at arbitrary positions on the cell body. Substrate contact and fibre geometry constrain early growth.

  2. The basal surface of a migrating cultured cell adheres to extracellular matrix while ghosted outlines move forward and an SMS2-like focus remains fixed at a substrate contact through an elongating retraction fibre.

    Relative-displacement dependence

    As the cell moves forward, SMS2 foci anchored at its basal leading edge remain on the substrate and come to lie on the trailing retraction fibres. Formation therefore depends in part on movement of the cell relative to the substrate.

  3. A nucleated cultured cell connects through a thin retraction fibre to a migrasome markedly smaller than the nucleus and containing only sparse cytosol-like cargo and intraluminal vesicles.

    Membrane origin and cargo

    Retraction fibres form a material-transport route between migrasomes and cells, providing a continuous source of plasma membrane and luminal contents. Proteins, nucleic acids, organelles, and secretory vesicles enter migrasomes through distinct transport and sorting mechanisms.

Stages of Formation

Migrasome Formation: From Nucleation to Maturation

  1. An SMS2-like transmembrane cluster occupies a localized lipid domain in the basal membrane, with shallow curvature and matrix anchoring.

    SMS2 nucleation

    At the basal leading edge, discrete SMS2 foci produce sphingomyelin and stay anchored to the substrate. Cell movement leaves these lipid sites on the retraction fibres.

  2. A continuous retraction-fiber membrane shows a coordinated precursor dome at left and a TSPAN/TEM-microdomain-rich expanded migrasome at right.

    Lipid- and integrin-mediated migrasome maturation

    PIP5K1A produces PI(4,5)P2, which recruits Rab35. Rab35 then binds the GFFKR motif of integrin α5, establishing an extracellular-matrix-facing anchoring axis.

    At this stage, the migrasome formally forms and begins to grow.

  3. A continuous retraction fiber expands from a smaller precursor into one large, matrix-anchored migrasome enriched in tetraspanin-like membrane clusters and sparse intraluminal vesicles.

    TEM-mediated membrane expansion and stabilization

    Tension fluctuations and retraction-fibre junctions promote membrane bulging, while Syt1 can stabilize early precursors in a calcium-dependent manner. TSPAN4 and other tetraspanins then co-assemble with cholesterol and sphingomyelin in the membrane to form TSPAN4-enriched microdomains (TEMs). TEMs further self-organize into TSPAN4-enriched macrodomains (TEMAs), continuously increasing local membrane bending rigidity, promoting structural expansion, and ultimately generating migrasome-like structures.