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JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation
Luis Bonet-Ponce1,2,3, Tsion Tegicho1,2, Nuria Fernandez-Martinez1,2
1Department of Neurology, The Neuroscience Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
The Journal of Cell Biology
|September 24, 2025
Summary
Parkinson's disease kinase LRRK2 regulates lysosomal tubulation. New research reveals RILPL1 opposes JIP4's action, controlling lysosomal tubule dynamics via microtubule motor proteins.
Area of Science:
- Cell Biology
- Molecular Neuroscience
- Organelle Dynamics
Background:
- Lysosomes are crucial organelles involved in cellular waste disposal and signaling.
- Lysosomal membrane remodeling is essential for cellular function and response to stress.
- The Parkinson's disease-associated kinase LRRK2 plays a role in lysosome regulation.
Purpose of the Study:
- To identify novel proteins involved in LRRK2-mediated lysosomal tubulation.
- To elucidate the opposing mechanisms regulating lysosomal tubule dynamics.
Main Methods:
- Proteomic analysis of lysosomes following LRRK2 kinase inhibition.
- Biochemical assays to study protein-protein interactions.
- Live-cell imaging to observe lysosomal tubule dynamics.
Main Results:
- RILPL1 is recruited to dysfunctional lysosomes dependent on LRRK2 kinase activity.
- RILPL1 binds to p150Glued and retracts lysosomal tubules towards the minus-end of microtubules.
- RILPL1 acts as an opposing motor adaptor protein to JIP4, which drives tubule extension.
Conclusions:
- Lysosomal tubulation is dynamically regulated by opposing motor adaptor proteins, JIP4 and RILPL1.
- These opposing forces create a metastable state, enabling dynamic lysosomal membrane remodeling.
- This study uncovers new regulators of lysosomal function and their role in cellular homeostasis.
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