Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Wednesday Speaker Abstracts

STRUCTURAL BASIS FOR ACTIVATION AND GATING OF IP3 RECEPTOR CALCIUM CHANNELS Erkan Karakas Vanderbilt University, USA No Abstract

FAT CHANCES: HOW A SIGNALING LIPID INFLUENCES LYSOSOMAL PH VIA THE CHLORIDE TRANSPORTER CLC-7 Joseph A. Mindell 1 ; 1 NINDS, NIH, Bethesda, MD, USA The acidic luminal pH of lysosomes, maintained within a narrow range, is essential for proper degrative function of the organelle and is generated by the action of a V-type H+ ATPase, but other pathways for ion movement are required to dissipate the voltage generated by this process. ClC-7, a Cl-/H+ antiporter responsible for lysosomal Cl- permeability, is a candidate to contribute to the acidification process as part of this “counterion pathway”. The signaling lipid PI(3,5)P2 modulates lysosomal dynamics, including by regulating lysosomal ion channels, raising the possibility that it could contribute to lysosomal pH regulation. Here we demonstrate that depleting PI(3,5)P2 by inhibiting the PIKfyve kinase causes lysosomal hyperacidification, primarily via an effect on ClC-7. We further show that PI(3,5)P2 directly inhibits ClC-7 transport and that this inhibition is eliminated in a disease-causing gain-of-function ClC-7 mutation. Together these observations suggest an intimate role for ClC-7 in lysosomal pH regulation.

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