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Chen CC, Krogsaeter E, Butz ES, et al. TRPML2 is an osmo/mechanosensitive cation channel in endolysosomal organelles. Sci Adv. 2020;6(46)doi: 10.1126/sciadv.abb5064.
Chen, C. C., Krogsaeter, E., Butz, E. S., Li, Y., Puertollano, R., Wahl-Schott, C., Biel, M., & Grimm, C. (2020). TRPML2 is an osmo/mechanosensitive cation channel in endolysosomal organelles. Science advances, 6(46), . https://doi.org/10.1126/sciadv.abb5064
Chen, Cheng-Chang, et al. "TRPML2 is an osmo/mechanosensitive cation channel in endolysosomal organelles." Science advances vol. 6,46 (2020). doi: https://doi.org/10.1126/sciadv.abb5064
Chen CC, Krogsaeter E, Butz ES, Li Y, Puertollano R, Wahl-Schott C, Biel M, Grimm C. TRPML2 is an osmo/mechanosensitive cation channel in endolysosomal organelles. Sci Adv. 2020 Nov 11;6(46). doi: 10.1126/sciadv.abb5064. Print 2020 Nov. PMID: 33177082; PMCID: PMC7673730.
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Sci Adv. 2020 Nov 11;6(46). doi: 10.1126/sciadv.abb5064. Print 2020 Nov.

TRPML2 is an osmo/mechanosensitive cation channel in endolysosomal organelles.

Science advances

Cheng-Chang Chen, Einar Krogsaeter, Elisabeth S Butz, Yanfen Li, Rosa Puertollano, Christian Wahl-Schott, Martin Biel, Christian Grimm

Affiliations

  1. Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany. [email protected] [email protected] [email protected].
  2. Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
  3. Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
  4. Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität, Munich, Germany.
  5. Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States.
  6. Institute for Neurophysiology, Hannover Medical School, Hannover, Germany.
  7. Walther Straub Institute of Pharmacology and Toxicology Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany. [email protected] [email protected] [email protected].

PMID: 33177082 PMCID: PMC7673730 DOI: 10.1126/sciadv.abb5064

Abstract

Endolysosomes are dynamic, intracellular compartments, regulating their surface-to-volume ratios to counteract membrane swelling or shrinkage caused by osmotic challenges upon tubulation and vesiculation events. While osmosensitivity has been extensively described on the plasma membrane, the mechanisms underlying endolysosomal surface-to-volume ratio changes and identities of involved ion channels remain elusive. Endolysosomes mediate endocytosis, exocytosis, cargo transport, and sorting of material for recycling or degradation. We demonstrate the endolysosomal cation channel TRPML2 to be hypotonicity/mechanosensitive, a feature crucial to its involvement in fast-recycling processes of immune cells. We demonstrate that the phosphoinositide binding pocket is required for TRPML2 hypotonicity-sensitivity, as substitution of L314 completely abrogates hypotonicity-sensitivity. Last, the hypotonicity-insensitive TRPML2 mutant L314R slows down the fast recycling pathway, corroborating the functional importance of hypotonicity-sensitive TRPML2. Our results highlight TRPML2 as an accelerator of endolysosomal trafficking by virtue of its hypotonicity-sensitivity, with implications in immune cell surveillance and viral trafficking.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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