Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams

Abstract

Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus-end directed kinesin and minus-end directed dynein motors. Microtubules are decorated by microtubule-associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer's disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single-molecule assays indicate that kinesin-1 is more strongly inhibited than kinesin-2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin-1, kinesin-2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus-end in a dose-dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin-1, kinesin-2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor-specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus- and minus-end directed transport.

Asymmetric Tug-of-War leads to Cooperative Transport of a Cargo by Multiple Kinesins

“…As the roadblock concentration increases from 0 to 30 to 100 nM, the proportion of stuck microtubule increases from 7% to 12% to 29%. The average velocity of the fast microtubules also decreases from 926 nm/sec to 857 nm/sec to 806 nm/sec, consistent with previous roadblock studies (Chaudhary, Berger, Berger, & Hendricks, 2018). Taken together, roadblocks reduce the average cargo velocity and induce pauses in a cargo moved by a team of kinesin.…”

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

“…Consistent with this notion, large puncta of microtubule-associated PR30 can act as obstacles for kinesin-1 and dynein, stimulating motor pausing or detachment. This effect is reminiscent of the ability of the MAPT (tau) protein to partition into patches on microtubules and obstruct the motility of kinesin-1 and dynein complexes in vitro (75)(76)(77)(78)(79). Mutations in both MAPT and C9orf72 have been shown to cause FTD (80) and it was recently proposed that this reflects a shared inhibitory effect on nucleocytoplasmic transport (81).…”

MAP7 recruits kinesin-1 to microtubules to direct organelle transport

“…We isolated phagosomes along with their native transport machinery, and reconstituted their motility along polarity-marked microtubules. Phagosomes are transported by teams of 1-3 kinesin-1, 2-6 kinesin-2, and 3-10 dynein motors (13,25).…”

“…For example, the neuronal MAP tau reduces kinesin-1 processivity (11,12). On cargoes transported bidirectionally by opposing kinesin and dynein motors, inhibition of kinesin-1 biases transport towards the microtubule minus end (13).…”