Regulation of in vivo dynein force production by CDK5 and 14-3-3ε and KIAA0528

Dail E. Chapman, Babu J. N. Reddy, Bunchhin Huy, Matthew J. Bovyn, Stephen John S. Cruz, Zahraa M. Al-Shammari, Han Han, Wenqi Wang, Deanna S. Smith and Steven P. Gross ()
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Dail E. Chapman: University of California
Babu J. N. Reddy: University of California
Bunchhin Huy: University of California
Matthew J. Bovyn: University of California
Stephen John S. Cruz: University of California
Zahraa M. Al-Shammari: University of California
Han Han: University of California
Wenqi Wang: University of California
Deanna S. Smith: University of South Carolina
Steven P. Gross: University of California

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Single-molecule cytoplasmic dynein function is well understood, but there are major gaps in mechanistic understanding of cellular dynein regulation. We reported a mode of dynein regulation, force adaptation, where lipid droplets adapt to opposition to motion by increasing the duration and magnitude of force production, and found LIS1 and NudEL to be essential. Adaptation reflects increasing NudEL-LIS1 utilization; here, we hypothesize that such increasing utilization reflects CDK5-mediated NudEL phosphorylation, which increases the dynein-NudEL interaction, and makes force adaptation possible. We report that CDK5, 14-3-3ε, and CDK5 cofactor KIAA0528 together promote NudEL phosphorylation and are essential for force adaptation. By studying the process in COS-1 cells lacking Tau, we avoid confounding neuronal effects of CDK5 on microtubules. Finally, we extend this in vivo regulatory pathway to lysosomes and mitochondria. Ultimately, we show that dynein force adaptation can control the severity of lysosomal tug-of-wars among other intracellular transport functions involving high force.

Date: 2019
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DOI: 10.1038/s41467-018-08110-z

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