RANKL-inducible Arl8b effector RUFY4 drives HOPS-mediated lysosomal maturation and trafficking in osteoclasts

Walia, Kshitiz and Kumar, Gaurav and Arya, Subhash B. and Chouhan, Priya and Kaur, Arshdeep and Gupta, Medha and Tuli, Amit (2026) RANKL-inducible Arl8b effector RUFY4 drives HOPS-mediated lysosomal maturation and trafficking in osteoclasts. MOLECULAR BIOLOGY OF THE CELL, 37 (5).

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Abstract

Osteoclast-mediated bone resorption depends on the secretion of lysosomal hydrolases via the fusion of secretory lysosomes with the ruffled border, yet the molecular mechanisms governing lysosomal trafficking and fusion remain incompletely understood. Here, we demonstrate that the small GTPase Arl8b regulates the processing of osteoclastspecific lysosomal hydrolase, cathepsin K, and the positioning of secretory lysosomes toward the actin ring. Accordingly, depletion of Arl8b led to defects in lysosome-mediated bone resorption in osteoclasts. We identify RUFY4 as a RANKL-inducible Arl8b effector that promotes lysosome clustering and maturation by linking Arl8b to Rab7 through the adaptor PLEKHM1 and recruiting the multi-subunit tethering factor HOPS complex to drive late endosome-lysosome fusion. Depletion of RUFY4 or HOPS subunits impairs cathepsin K processing and disrupts lysosome positioning, leading to reduced bone resorption activity. These findings suggest that Arl8b and its interaction partners play essential roles in biogenesis and positioning of secretory lysosomes, essential for osteoclast function in bone remodeling.

Item Type:	Article
Additional Information:	copyright of this article belongs to AMER SOC CELL BIOLOGY
Subjects:	Q Science > QR Microbiology
Depositing User:	Dr. K.P.S.Sengar
Date Deposited:	16 Jul 2026 04:05
Last Modified:	16 Jul 2026 04:05
URI:	http://crdd.osdd.net/open/id/eprint/3453

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