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

Author

Listed:
  • Wing-Cheung Chan

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Qian Zhao

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Koon Ho Wong

    (University of Macau, Avenida da Universidade, Taip
    University of Macau, Avenida da Universidade, Taipa
    University of Macau, Avenida da Universidade, Taipa)

  • Hok-Him Tang

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Daniel Kam-Wah Mok

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Lakhansing Pardeshi

    (University of Macau, Avenida da Universidade, Taip
    University of Macau, Avenida da Universidade, Taipa)

  • Ye Chun Ruan

    (The Hong Kong Polytechnic University)

  • Yang Yang

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Chi-Ming Wong

    (The Hong Kong Polytechnic University)

  • Clarence T. T. Wong

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Yong-Juan Zhao

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Ka Ying Chan

    (The Hong Kong Polytechnic University)

  • Zengsheng Yin

    (The University of Hong Kong
    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
    The Hong Kong Polytechnic University)

  • Franco King-Chi Leung

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University
    Hong Kong Science Park)

  • Ying-Ying Lui

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University
    Hong Kong Science Park)

  • 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
    The Hong Kong Polytechnic University)

  • Yu-Hin Ho

    (The University of Hong Kong
    The University of Hong Kong)

  • Xiang-Yang Ye

    (Hangzhou Normal University
    Hangzhou Normal University
    Hangzhou Normal University
    Hangzhou Normal University)

  • Man Lung Yeung

    (The University of Hong Kong)

  • Yajing Zhang

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Yan Xiang Zhao

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Jiang Liu

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Ka-Hing Wong

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Larry M. C. Chow

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

  • Xiang David Li

    (The University of Hong Kong
    The University of Hong Kong)

  • Gary M. Tse

    (The Chinese University of Hong Kong)

  • Man-Kin Wong

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University
    Hong Kong Science Park)

  • Xiao Shen

    (Ltd)

  • Pauline Chiu

    (The University of Hong Kong
    The University of Hong Kong)

  • Ben C. B. Ko

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

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.

Suggested Citation

  • 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 &, 2025. "Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61565-9
    DOI: 10.1038/s41467-025-61565-9
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