2. Academic Validation
  3. Endolysosomal channel TMEM175 mediates antitoxin activity of DABMA

Endolysosomal channel TMEM175 mediates antitoxin activity of DABMA

  • FEBS J. 2024 Sep;291(18):4142-4154. doi: 10.1111/febs.17242.
Yu Wu 1 2,  Jiamin Huang 3,  Fei Zhang 3,  Florence Guivel-Benhassine 4,  Mathieu Hubert 4,  Olivier Schwartz 4,  Weihua Xiao 3,  Jean-Christophe Cintrat 5,  Lili Qu 3,  Julien Barbier 2,  Daniel Gillet 2,  Chunlei Cang 1 3
Affiliations

Affiliations

  • 1 Institute of Health and Medicine, Hefei Comprehensive National Science Center, China.
  • 2 Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France.
  • 3 The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.
  • 4 Unité virus et immunité, Département de Virologie, Institut Pasteur, Paris, France.
  • 5 Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SCBM, Gif-sur-Yvette, France.
PMID: 39097908 DOI: 10.1111/febs.17242
Abstract

DABMA is a chemical molecule optimized from the parent compound ABMA and exhibits broad-spectrum antipathogenic activity by modulating the host's endolysosomal and autophagic pathways. Both DABMA and ABMA inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cellular assay, which further expands their anti-pathogen spectrum in vitro. However, their precise mechanism of action has not yet been resolved. TMEM175 is a newly characterized endolysosomal channel which plays an essential role in the homeostasis of endosomes and lysosomes as well as organelle fusion. Here, we show that DABMA increases the endosomal TMEM175 current through organelle patch clamping with an EC50 of 17.9 μm. Depletion of TMEM175 protein significantly decreases the antitoxin activity of DABMA and affects its action on acidic- and Rab7-positive endosomes as well as on endolysosomal trafficking. Thus, TMEM175 is necessary for DABMA's activity and may represent a druggable target for the development of anti-infective drugs. Moreover, DABMA, as an activator of the TMEM175 channel, may be useful for the in-depth characterization of the physiological and pathological roles of this endolysosomal channel.

Keywords

DABMA; TMEM175 channel; broad‐spectrum anti‐infective; endosome; lysosome.

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