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Tetrandrine regulates NAADP-mediated calcium signalling through a novel LIMP-2-dependent, sphingosine-mediated mechanism

ABSTRACT: Tetrandrine (Tet) is a highly potent inhibitor of Ebola virus replication by blocking NAADP-dependent calcium release through endolysosomal two-pore channels (TPCs) and is a moderately potent anti-tumor agent. Using a clickable, photoaffinity probe of Tet, we identified lysosomal integral membrane protein-2 (LIMP-2) as the genuine molecular target of Tet and a novel regulator for NAADP-dependent calcium release. Tet binds to the ectodomain of LIMP-2 and inhibits its cholesterol and sphingosine transport function, resulting in the alteration of lipid profiles and metabolic pathways in cells and development of acute hypercholesterolemia and hepatosteatosis in mice. Cells treated with Tet or depleted for LIMP-2 similarly inhibits NAADP-dependent calcium release, which can be restored by eliminating lysosomal cholesterol and sphingosines. Importantly, addition of sphingosine dose-dependently triggers lysosomal calcium release through TPCs, and restores NAADP-dependent calcium release in Tet-treated or LIMP-2-depleted cells. At higher concentrations, Tet induced apoptosis associated with unfolded protein response activation in a LIMP-2-independent manner. We identified Tet as the first known inhibitor of LIMP-2, discerned its pharmacological principle in regulating calcium signalling and cell death, and discovered a novel LIMP-2-regulated, sphingosine-dependent lysosomal calcium signalling pathway. Our findings have profound implications in the understanding of lysosomal calcium signalling mechanisms and development of Tet and LIMP-2 inhibitors into clinical therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212648 | GEO | 2023/03/04

REPOSITORIES: GEO

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Tetrandrine regulates NAADP-mediated calcium signalling through a novel LIMP-2-dependent, sphingosine-mediated mechanism

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