Metazoan are characterized by tissue composed of organized arrangements of specialized cells. The logistics of generating and maintaining tissue are heavily dependent on distinct aspects of trafficking. Specifically, polarized trafficking is required for the cell structures responsible for tissue generation and maintenance. In this pathway, the conserved molecular machinery of the exocyst integrates signaling from lipid and protein regulatory factors. This activity results in tethering vesicles to the plasma membrane for their eventual fusion and cargo delivery. However, the molecular mechanisms of this process are poorly defined. To determine the mechanics and regulation of tethering in polarized trafficking, we have reconstituted the entire system alongside validating experimental cell biology. Our data provide a molecular mechanism of exocyst-mediated tethering, and a unique functional requirement for phosphoinositide signaling on late-stage vesicles in the vicinity of the plasma membrane. Finally, to address polarized trafficking in the context of cell organizational processes, we examine the reprogramming of exocyst regulation in epithelial to mesenchymal transition. Altogether, our work aims to generate principles holistically linking the programming of molecular mechanism to outcomes at a tissue scale.

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