Kazrin is an endosomal adaptor for dynein/dynactin

Kazrin is a protein widely expressed in vertebrates whose depletion causes a myriad of developmental defects, in part derived from altered cell adhesion, impaired cell migration and failure to undergo Epidermal to Mesenchymal Transition (EMT). However, the primary molecular role of kazrin, which might contribute to all these functions, has not been elucidated yet. We previously identified one of its isoforms, kazrin C, as a protein that potently inhibits clathrin-mediated endocytosis when overexpressed. We now generated kazrin knock out Mouse Embryonic Fibroblasts (MEFs) to investigate its endocytic function. We found that kazrin depletion delays perinuclear enrichment of internalized material, indicating a role in endocytic traffic from Early (EE) to Recycling Endosomes (REs). Consistently, we found that the C-terminal domain of kazrin C, predicted to be an Intrinsically Disordered Region (IDR), directly interacts with several components of the EEs, and that kazrin depletion impairs centripetal motility of EEs. Further, we noticed that the N-terminus of kazrin C shares homology with dynein/dynactin adaptors and that it directly interacts with the dynactin complex and the dynein Light Intermediate Chain 1 (LIC1). Altogether, the data indicate that one of the primary kazrin functions is to facilitate endocytic recycling via the perinuclear endocytic compartment, by promoting microtubule and dynein/dynactin-dependent transport of EEs or EE-derived transport intermediates to the RE.