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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月8日

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  • 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,
  • Ben C. B. Ko

摘要

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.