RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin

Tal Keren-Kaplan, Amra Sarić, Saikat Ghosh, Chad D. Williamson, Rui Jia, Yan Li and Juan S. Bonifacino ()
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Tal Keren-Kaplan: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Amra Sarić: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Saikat Ghosh: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Chad D. Williamson: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Rui Jia: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Yan Li: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Juan S. Bonifacino: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract The small GTPase ARL8 associates with endolysosomes, leading to the recruitment of several effectors that couple endolysosomes to kinesins for anterograde transport along microtubules, and to tethering factors for eventual fusion with other organelles. Herein we report the identification of the RUN- and FYVE-domain-containing proteins RUFY3 and RUFY4 as ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin for retrograde transport along microtubules. Using various methodologies, we find that RUFY3 and RUFY4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3 and RUFY4 promote concentration of endolysosomes in the juxtanuclear area of non-neuronal cells, and drive redistribution of endolysosomes from the axon to the soma in hippocampal neurons. The function of RUFY3 in retrograde transport contributes to the juxtanuclear redistribution of endolysosomes upon cytosol alkalinization. These studies thus identify RUFY3 and RUFY4 as ARL8-dependent, dynein-dynactin adaptors or regulators, and highlight the role of ARL8 in the control of both anterograde and retrograde endolysosome transport.

Date: 2022
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DOI: 10.1038/s41467-022-28952-y

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