ORIGINAL RESEARCH article
Front. Mol. Biosci.
Sec. Molecular Recognition
This article is part of the Research TopicReviews in ARF, the most misunderstood G protein I ever knew: a collection of papers exploring the multifaceted functions of an ancient protein familyView all 3 articles
Loss of ARF5 impairs recovery after lysosomal damage
Provisionally accepted
- 1University of Virginia, Charlottesville, United States
- 2Uniwersytet Gdanski, Gdańsk, Poland
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ABSTRACT Lysosomal dysfunction is a defining feature of aging and neurodegenerative diseases, where lysosomal membrane permeabilization and release of their contents can trigger cellular death pathways. To counteract this, cells rely on lysosomal quality control mechanisms, many of which depend on lipid delivery to repair damaged membranes. However, the regulatory pathways governing this process remain unclear. In this study, we investigated whether canonical ARF GTPases, best known for their roles in Golgi and endosomal vesicular trafficking, are recruited to damaged lysosomes and contribute to their repair. Using LysoIP-based lysosome isolation, super-resolution immunofluorescence imaging, and functional assays in HeLa and HEK293 cells, we found that ARF1, ARF5, and ARF6 localize to lysosomal membranes following L-leucyl-L-leucine methyl ester (LLOME)-induced permeabilization. While loss of ARF6 did not impair recovery, ARF5 depletion resulted in a nearly complete block of lysosomal repair. These findings identify ARF proteins as early responders to lysosomal damage and suggest isoform-specific roles in coordinating the pathways of lysosomal quality control.
Keywords: ARF, Lysosome, repair, OSBP, ORP
Received: 04 Sep 2025; Accepted: 08 Oct 2025.
Copyright: © 2025 Casanova, Iwaniec and Bott. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: James E. Casanova, jec9e@virginia.edu
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