Intracellular nanovesicles mediate integrin trafficking during cell migration

Membrane traffic is an important regulator of cell migration through the endocytosis and recycling of cell surface receptors such as integrin heterodimers. Intracellular nanovesicles (INVs), are a recently identified class of transport vesicle that are involved in multiple membrane trafficking steps including the recycling pathway. The only known marker for INVs is Tumor Protein D54 (TPD54/TPD52L2), a member of the TPD52-like protein family. Overexpression of TPD52-like family proteins in cancer has been linked to poor prognosis and an aggressive metastatic phenotype which suggests cell migration may be altered under these conditions. Here we show that TPD54 associates with INVs by directly binding high curvature membrane via a conserved positively charged motif in its C-terminus. We describe how other members of the TPD52-like family are also associated with INVs and we document the Rab GTPase complement of all INVs. Depletion of TPD52-like proteins inhibits cell migration and invasion; and we show that this is likely due to altered integrin recycling. Our study highlights the involvement of INVs in the trafficking of cell surface proteins to generate biologically important outputs in health and disease.