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

Wing-Cheung Chan, Qian Zhao, Koon Ho Wong, Hok-Him Tang, Daniel Kam-Wah Mok, Lakhansing Pardeshi, Ye Chun Ruan, Yang Yang, Chi-Ming Wong, Clarence T. T. Wong, Yong-Juan Zhao, Ka Ying Chan, Zengsheng Yin, Howard Ho-Wai Leung, Xiyang Ma, Mary P. Chau, Franco King-Chi Leung, Ying-Ying Lui, Shannon Wing-Ngor Au, Kailei Sun, Chin Yu Mok, Fang Wang, Cong Ma, Yu-Hin Ho, Xiang-Yang Ye, Man Lung Yeung, Yajing Zhang, Yan Xiang Zhao, Jiang Liu, Ka-Hing Wong, Larry M. C. Chow, Xiang David Li, Gary M. Tse, Man-Kin Wong, Xiao Shen, Pauline Chiu () and Ben C. B. Ko ()
Additional contact information
Wing-Cheung Chan: The Hong Kong Polytechnic University
Qian Zhao: The Hong Kong Polytechnic University
Koon Ho Wong: University of Macau, Avenida da Universidade, Taip
Hok-Him Tang: The Hong Kong Polytechnic University
Daniel Kam-Wah Mok: The Hong Kong Polytechnic University
Lakhansing Pardeshi: University of Macau, Avenida da Universidade, Taip
Ye Chun Ruan: The Hong Kong Polytechnic University
Yang Yang: The Hong Kong Polytechnic University
Chi-Ming Wong: The Hong Kong Polytechnic University
Clarence T. T. Wong: The Hong Kong Polytechnic University
Yong-Juan Zhao: The Chinese University of Hong Kong
Ka Ying Chan: The Hong Kong Polytechnic University
Zengsheng Yin: The University of Hong Kong
Howard Ho-Wai Leung: The Chinese University of Hong Kong
Xiyang Ma: The Hong Kong Polytechnic University
Mary P. Chau: The Hong Kong Polytechnic University
Franco King-Chi Leung: The Hong Kong Polytechnic University
Ying-Ying Lui: The Hong Kong Polytechnic University
Shannon Wing-Ngor Au: The Chinese University of Hong Kong
Kailei Sun: The Chinese University of Hong Kong
Chin Yu Mok: The Chinese University of Hong Kong
Fang Wang: University of Macau, Avenida da Universidade, Taip
Cong Ma: The Hong Kong Polytechnic University
Yu-Hin Ho: The University of Hong Kong
Xiang-Yang Ye: Hangzhou Normal University
Man Lung Yeung: The University of Hong Kong
Yajing Zhang: The Hong Kong Polytechnic University
Yan Xiang Zhao: The Hong Kong Polytechnic University
Jiang Liu: The Hong Kong Polytechnic University
Ka-Hing Wong: The Hong Kong Polytechnic University
Larry M. C. Chow: The Hong Kong Polytechnic University
Xiang David Li: The University of Hong Kong
Gary M. Tse: The Chinese University of Hong Kong
Man-Kin Wong: The Hong Kong Polytechnic University
Xiao Shen: Ltd
Pauline Chiu: The University of Hong Kong
Ben C. B. Ko: The Hong Kong Polytechnic University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61565-9

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