Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis

Chouhan, Priya and Phogat, Yogita and Walia, Kshitiz and Debnath, Saikat and Choubey, Sandeep and Gupta, Medha and Tuli, Amit and Sharma, Mahak (2026) Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis. J. Cell Biol., 225 (7).

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Abstract

The small GTP-binding protein Arl8b is established as a regulator of lysosome positioning and fusion, yet its role in lysosome biogenesis remains unclear. Here, we investigate the role of Arl8b in the trafficking of newly synthesized LAMP1 to lysosomes using the Retention Using Selective Hook (RUSH) assay. We find that Arl8b localizes to post-endocytic LAMP1-containing vesicles prior to fusion with acidic lysosomes. Arl8b depletion leads to Rab11a-dependent recycling of LAMP1 to the plasma membrane, impairing its lysosomal delivery. Mechanistically, Arl8b recruits the Rab11a GAP, TBC1D9B, to LAMP1-positive membranes, and TBC1D9B depletion similarly disrupts LAMP1 sorting. Notably, TBC1D9B knockdown also impairs the retrieval of cation-independent mannose-6-phosphate receptor (CI-M6PR) from Rab11a- and Rab14-positive endosomes to the trans-Golgi network, impairing pro-cathepsin trafficking and cargo degradation. These findings reveal that Arl8b-mediated recruitment of Rab GAP TBC1D9B is crucial for inactivation of the Rab11a recycling pathway, leading to efficient sorting of lysosomal cargo to their functional location.

Item Type:	Article
Additional Information:	Copyright of this article belongs to Rockefeller University Press
Subjects:	Q Science > QR Microbiology
Depositing User:	Dr. K.P.S.Sengar
Date Deposited:	20 Jul 2026 08:19
Last Modified:	20 Jul 2026 08:22
URI:	http://crdd.osdd.net/open/id/eprint/3480

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