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Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism

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Published in:Nature Communications vol. 16, no. 1 (2025), p. 6308
Main Author: Chan, Wing-Cheung
Other Authors: Zhao, Qian, Wong, Koon Ho, Tang, Hok-Him, Mok, Daniel Kam-Wah, Pardeshi, Lakhansing, Ruan, Ye Chun, Yang, Yang, Wong, Chi-Ming, Wong, Clarence T. T., Zhao, Yong-Juan, Chan, Ka Ying, Yin, Zengsheng, Leung, Howard Ho-Wai, Ma, Xiyang, Chau, Mary P., Leung, Franco King-Chi, Lui, Ying-Ying, Au, Shannon Wing-Ngor, Sun, Kailei, Mok, Chin Yu, Wang, Fang, Ma, Cong, Ho, Yu-Hin, Ye, Xiang-Yang, Yeung, Man Lung, Zhang, Yajing, Zhao, Yan Xiang, Liu, Jiang, Wong, Ka-Hing, Chow, Larry M. C., Li, Xiang David, Tse, Gary M., Wong, Man-Kin, Shen, Xiao, Chiu, Pauline, Ko, Ben C. B.
Published:
Nature Publishing Group
Subjects:
Endoplasmic reticulum
Cholesterol
Calcium signalling
Lipid metabolism
Tetrandrine
Ebola virus
Labeling
Chemistry
Homeostasis
Mitochondria
Protein folding
Viral diseases
Peptides
Localization
Cell culture
NAADP
Calcium
Proteins
Cell death
Apoptosis
Lipids
Calcium homeostasis
Ebolavirus
Environmental
Online Access:Citation/Abstract
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Abstract:Tetrandrine (Tet) is a potent inhibitor of Ebola virus replication by blocking NAADP-dependent calcium release through endolysosomal two-pore channels (TPCs) and a moderately potent anti-tumor agent. Using a clickable photoaffinity probe, we identify lysosomal integral membrane protein-2 (LIMP-2) as a direct target of Tet and a key regulator of this calcium signaling. Tet binds LIMP-2’s ectodomain, inhibiting lysosomal cholesterol and sphingosine transport, which alters lipid metabolism. Tet treatment and LIMP-2 depletion inhibit NAADP-dependent calcium release, reversible by removing lysosomal cholesterol and sphingosine. Sphingosine triggers lysosomal calcium release via TPCs and restores this signaling in Tet-treated or LIMP-2-deficient cells, revealing a LIMP-2-regulated, sphingosine-dependent lysosomal calcium pathway. At higher doses, Tet induces apoptosis through unfolded protein response activation independently of LIMP-2. These findings highlight Tet as a LIMP-2 inhibitor, elucidate its role in calcium signaling and cell death, and suggest therapeutic potential for Tet and LIMP-2 inhibitors in antiviral treatments.Tetrandrine is one of the most potent inhibitors of Ebola Virus infection. Here the authors identify LIMP-2 as a direct cellular target of Tetrandrine and establish a functional connection between lysosomal sphingosine homeostasis and calcium regulation.
ISSN:2041-1723
DOI:10.1038/s41467-025-61565-9
Source:Health & Medical Collection