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Collapse of late endosomal pH elicits a rapid Rab7 response via V-ATPase and RILP
R J Mulligan1,2,3, M M Magaj4,2, L Digilio1
1Department of Cell Biology, University of Virginia, Charlottesville, VA.
Biorxiv : the Preprint Server for Biology
|November 14, 2023
Summary
The dipeptide LLOMe neutralizes late endosome pH, activating Rab7 and disrupting protein receptor recycling. This reveals a new pathway involving V-ATPase and RILP in endosomal pH regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Endosomal-lysosomal trafficking relies on proton pump (H+-V-ATPase) acidification for lysosomal function and proteostasis.
- Disrupted endosomal pH impairs cellular protein balance and function.
Approach:
- Investigated the effect of the dipeptide LLOMe on late endosomes (LEs).
- Utilized ammonium chloride (NH4Cl) and Rab7 hyperactive mutants to mimic LLOMe's effects.
- Examined the interaction between V-ATPase, RILP, and Rab7.
Key Points:
- LLOMe neutralizes LE pH without membrane permeabilization, unlike its known lysosomal effect.
- LLOMe causes Rab7 hyper-activation, disrupting endosomal tubulation and CI-M6PR recycling.
- pH neutralization enhances V1G1-V-ATPase assembly, stabilizing GTP-bound Rab7 via RILP.
Conclusions:
- A novel pathway is proposed where V-ATPase and RILP coordinate LE pH and Rab7 activation.
- This mechanism may regulate endosomal maturation, starvation responses, and disease-related pH changes.
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