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Peer-reviewedCC BYThe Journal of cell biology

ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.

  • Devin Clegg1,2,3,4,5
  • Amanda Bentley-DeSousa1,2,3,4,5
  • Agnes Roczniak-Ferguson1,2,3,4,5
  • Shawn M Ferguson1,2,3,4,6,5
6 affiliations
  1. 1Departments of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
  2. 2Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
  3. 3Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA.
  4. 4Wu Tsai Institute, Yale University School of Medicine , New Haven, CT, USA.
  5. 5Aligning Science Across Parkinson's (ASAP) Collaborative Research Network , Chevy Chase, MD, USA.
  6. 6Kavli Institute for Neuroscience, Yale University School of Medicine , New Haven, CT, USA.
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Abstract

Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the accumulation of multiple Rab GTPases on lysosomes. LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7-dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.

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Cite

BibTeXRIS
BibTeX
@article{clegg2026clc7,
  title = {{ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.}},
  author = {Devin Clegg and Amanda Bentley-DeSousa and Agnes Roczniak-Ferguson and Shawn M Ferguson},
  journal = {The Journal of cell biology},
  year = {2026},
  month = oct,
  doi = {10.1083/jcb.202511137},
  url = {https://europepmc.org/article/MED/42900584},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.
AU  - Devin Clegg
AU  - Amanda Bentley-DeSousa
AU  - Agnes Roczniak-Ferguson
AU  - Shawn M Ferguson
PY  - 2026
DA  - 2026/10/20
JO  - The Journal of cell biology
DO  - 10.1083/jcb.202511137
UR  - https://europepmc.org/article/MED/42900584
AB  - Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the accumulation of multiple Rab GTPases on lysosomes. LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7-dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.
SN  - 0021-9525
SN  - 1540-8140
ER  -