The types and numbers of kinesins and dyneins transporting endocytic cargoes modulate their motility and response to tau

• Published in: The Journal of biological chemistry Vol. 300; no. 6; p. 107323
• Main Authors: Beaudet, Daniel, Berger, Christopher L., Hendricks, Adam G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2024; American Society for Biochemistry and Molecular Biology
• Subjects: dynein; in vitro reconstitution; kinesin; mathematical modeling; microtubule-associated protein (MAP); optical tweezers; organelle transport; tau protein (tau); microtubule-associated protein (MAP); DDB; CDF; LP; kinesin; EP; TIRF; MAB; dynein; BSA; in vitro reconstitution; mathematical modeling; optical tweezers; organelle transport; MAP; tau protein (tau); MSD; Tau protein (Tau); in vitro reconstitution
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2024.107323

Organelles and vesicular cargoes are transported by teams of kinesin and dynein motors along microtubules. We isolated endocytic organelles from cells at different stages of maturation and reconstituted their motility along microtubules in vitro. We asked how the sets of motors transporting a cargo determine its motility and response to the microtubule-associated protein tau. Here, we find that phagosomes move in both directions along microtubules, but the directional bias changes during maturation. Early phagosomes exhibit retrograde-biased transport while late phagosomes are directionally unbiased. Correspondingly, early and late phagosomes are bound by different numbers and combinations of kinesins-1, -2, -3, and dynein. Tau stabilizes microtubules and directs transport within neurons. While single-molecule studies show that tau differentially regulates the motility of kinesins and dynein in vitro, less is known about its role in modulating the trafficking of endogenous cargoes transported by their native teams of motors. Previous studies showed that tau preferentially inhibits kinesin motors, which biases late phagosome transport towards the microtubule minus-end. Here, we show that tau strongly inhibits long-range, dynein-mediated motility of early phagosomes. Tau reduces forces generated by teams of dynein motors on early phagosomes and accelerates dynein unbinding under load. Thus, cargoes differentially respond to tau, where dynein complexes on early phagosomes are more sensitive to tau inhibition than those on late phagosomes. Mathematical modeling further explains how small changes in the number of kinesins and dynein on cargoes impact the net directionality but also that cargoes with different sets of motors respond differently to tau.