Institute of Health and Medicine, Hefei Comprehensive National Science Center, China.
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France.
FEBS J. 2024 Sep;291(18):4142-4154. doi: 10.1111/febs.17242. Epub 2024 Aug 4.
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 EC 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.
DABMA 是一种从母体化合物 ABMA 优化而来的化学分子，通过调节宿主的内体和自噬途径，表现出广谱抗病原体活性。DABMA 和 ABMA 都在细胞检测中抑制严重急性呼吸综合征冠状病毒 2（SARS-CoV-2），这进一步扩大了它们在体外的抗病原体谱。然而，它们的确切作用机制尚未得到解决。TMEM175 是一种新鉴定的内体通道，在内涵体和溶酶体的动态平衡以及细胞器融合中发挥着重要作用。在这里，我们通过细胞器片钳实验显示，DABMA 通过增加内体 TMEM175 电流，其 EC 值为 17.9μm。TMEM175 蛋白的耗竭显著降低了 DABMA 的抗毒素活性，并影响其对酸性和 Rab7 阳性内涵体以及内体-溶酶体运输的作用。因此，TMEM175 是 DABMA 活性所必需的，可能代表了开发抗感染药物的可药物靶标。此外，DABMA 作为 TMEM175 通道的激活剂，可能有助于深入研究该内体通道的生理和病理作用。
