CCSer2 gates dynein activity at the cell periphery.

Cytoplasmic dynein-1 (dynein) is a microtubule-associated, minus end-directed motor that traffics hundreds of different cargos. Dynein must discriminate between cargos and traffic them at the appropriate time from the correct cellular region. How dynein's trafficking activity is regulated in time or cellular space remains poorly understood. Here, we identify CCSer2 as the first known protein to gate dynein activity in the spatial dimension. CCSer2 promotes the migration of developing zebrafish primordium cells, macrophages, and cultured human cells by facilitating the trafficking of cargos that are acted on by peripherally localized dynein. Our data suggest that CCSer2 disfavors the interaction between dynein and its regulator Ndel1 at the cell edge, resulting in localized dynein activation. These findings support a model where the spatial specificity of dynein is achieved by the localization of proteins that trigger Ndel1's release from dynein. We propose that CCSer2 defines a broader class of proteins that activate dynein in distinct microenvironments via regulating Ndel1-dynein interaction.