TRPML2 channel modulation by PI(3,5)P₂ and small-molecule agonists controls endosomal vesicle dynamics
Journal
Biomedicine and Pharmacotherapy
Journal Volume
189
Start Page
118350
ISSN
0753-3322
Date Issued
2025-08
Author(s)
Gu, Zi-Qi
Wang, Hsuan-Ti
Li, Yanfen
Krogsaeter, Einar
Lin, Alice C.
Lin, Jackson
Liu, Yi-Shan
Lin, Wei-Shuan
Burton, William
Liu, Mu-Lin
Feldmann, Colin
Tang, Rachel
Po, Ching-Wen
Hou, Pei-Shan
Yang, Zhuo
Keller, Marco
Leser, Charlotte
Fenske, Stefanie
Bracher, Franz
Wahl-Schott, Christian
Galione, Antony
Tsai, Yu-Huan
Grimm, Christian
Biel, Martin
Abstract
TRPML2 is an endolysosomal calcium-permeable channel gated by phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂). However, its subcellular localization and functional contribution to compartment-specific vesicle trafficking remain incompletely defined. In this study, we identify Rab4-positive recycling endosomes as a key site of TRPML2 activity and regulation. We further examined a PI(3,5)P₂-insensitive TRPML2 mutant (R310A), which exhibited reduced channel activity, accumulated perinuclear vesicles, and impaired Rab4 + endosomal motility. To restore channel function, we employed two selective small-molecule TRPML2 agonists, ML2-SA1 and ML2-SA2. Endolysosomal patch-clamp recordings confirmed that both compounds activate wild-type TRPML2 and effectively restore channel activity in the R310A mutant. Functional imaging further demonstrated that ML2-SA2 treatment rescues vesicle redistribution, reduces Golgi accumulation, and promotes peripheral vesicle dynamics. Notably, these effects were observed even in the absence of functional PI(3,5)P₂ gating, indicating that small-molecule agonists can bypass endogenous lipid regulation to restore TRPML2 activity. Our findings identify TRPML2 as a druggable ion channel whose activity is essential for maintaining Rab4-dependent vesicle trafficking. This study establishes a mechanistic link between phosphoinositide sensitivity, TRPML2 activation, and endosomal motility, and highlights a potential therapeutic strategy for correcting trafficking defects caused by impaired lipid signaling in immune cells or other pathophysiological contexts involving endosomal stress.
Subjects
TRPML
Phosphoinositides (PIPs)
Endosomal trafficking
Host defense
Publisher
Elsevier BV
Type
journal article