The sets of kinesins and dynein transporting endocytic cargoes determine the effect of tau on their motility

The misregulation of tau, a neuronal microtubule-associated protein, is linked to defective axonal transport and neurodegenerative disease. We reconstituted the motility of isolated phagosomes along microtubules to ask how the sets of motors transporting a cargo determine its motility and response to tau. Using quantitative photobleaching, we find that early phagosomes (EPs) and late phagosomes (LPs) are associated with different sets of kinesin-1, -2, -3, and dynein. While EPs exhibit unidirectional retrograde transport, LPs move bidirectionally. Previously, we found that tau biases LP transport towards the microtubule minus-end. Here, we find that tau strongly inhibits long-range retrograde EP motility. Tau impedes the forces generated by multi-dynein teams and accelerates dynein unbinding under load. Thus, specific cargoes differentially respond to tau, where dynein-complexes on EPs are more sensitive to tau than those on LPs.