Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance
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+...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74136 |
| _version_ | 1818025781806235648 |
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| author | Xavier Leray Jacob K Hilton Kamsi Nwangwu Alissa Becerril Vedrana Mikusevic Gabriel Fitzgerald Anowarul Amin Mary R Weston Joseph A Mindell |
| author_facet | Xavier Leray Jacob K Hilton Kamsi Nwangwu Alissa Becerril Vedrana Mikusevic Gabriel Fitzgerald Anowarul Amin Mary R Weston Joseph A Mindell |
| author_sort | Xavier Leray |
| collection | DOAJ |
| description | 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 kinase PIKfyve 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. |
| first_indexed | 2024-12-10T04:21:34Z |
| format | Article |
| id | doaj.art-ba99f83a0c944e9299218d4891a98871 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:21:34Z |
| publishDate | 2022-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ba99f83a0c944e9299218d4891a988712022-12-22T02:02:24ZengeLife Sciences Publications LtdeLife2050-084X2022-06-011110.7554/eLife.74136Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenanceXavier Leray0https://orcid.org/0000-0003-2107-6082Jacob K Hilton1https://orcid.org/0000-0003-1931-9516Kamsi Nwangwu2https://orcid.org/0000-0002-3446-8539Alissa Becerril3Vedrana Mikusevic4https://orcid.org/0000-0002-9666-9571Gabriel Fitzgerald5Anowarul Amin6Mary R Weston7Joseph A Mindell8https://orcid.org/0000-0002-6952-8247Membrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesMembrane Transport Biophysics Section, National Institute of Neurological Disorders and Stroke, Bethesda, United StatesThe 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 kinase PIKfyve 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.https://elifesciences.org/articles/74136lysosomeClC-7phosphoinositidechloridepH |
| spellingShingle | Xavier Leray Jacob K Hilton Kamsi Nwangwu Alissa Becerril Vedrana Mikusevic Gabriel Fitzgerald Anowarul Amin Mary R Weston Joseph A Mindell Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance eLife lysosome ClC-7 phosphoinositide chloride pH |
| title | Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance |
| title_full | Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance |
| title_fullStr | Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance |
| title_full_unstemmed | Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance |
| title_short | Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance |
| title_sort | tonic inhibition of the chloride proton antiporter clc 7 by pi 3 5 p2 is crucial for lysosomal ph maintenance |
| topic | lysosome ClC-7 phosphoinositide chloride pH |
| url | https://elifesciences.org/articles/74136 |
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