Kazrin promotes dynein/dynactin-dependent traffic from early to recycling endosomes

Kazrin is a protein widely expressed in vertebrates whose depletion causes a myriad of developmental defects, in part derived from altered cell adhesion and migration, as well as failure to undergo epidermal to mesenchymal transition. 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 to investigate its endocytic function. We found that kazrin depletion delays juxtanuclear enrichment of internalized material, indicating a role in endocytic traffic from early to recycling endosomes. Consistently, we found that the C-terminal domain of kazrin C, predicted to be an intrinsically disordered region, directly interacts with several early endosome (EE) components, and that kazrin depletion impairs retrograde motility of these organelles. 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. Altogether, the data indicate that one of the primary kazrin functions is to facilitate endocytic recycling by promoting dynein/dynactin-dependent transport of EEs or EE-derived transport intermediates to the recycling endosomes.

Automated summary

This study found that Kazrin plays an important role in vertebrate development, including cell adhesion, migration, and endocytic trafficking. The isoform Kazrin C was identified as a potent inhibitor of clathrin-mediated endocytosis when overexpressed. By generating Kazrin knockout mouse embryonic fibroblasts, the researchers discovered that Kazrin depletion delays the transport of internalized material and impairs the retrograde motility of early endosomes. Further analysis revealed that the C-terminal domain of Kazrin C interacts with early endosome components and that the N-terminus shares homology with dynein/dynactin adaptors. Overall, these findings suggest that Kazrin facilitates endocytic recycling by promoting dynein/dynactin-dependent transport of early endosomes or their derivatives.