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Tetrandrine is a novel inhibitor of NAADP-induced calcium release through targeting Lysosomal Integral Membrane Protein 2 (LIMP-2)

ABSTRACT: Tetrandrine (Tet), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra, has been implicated in a broad range of pharmacological activities, and is best known for its highly potent activity against Ebola virus infection by inhibiting NAADP-mediated calcium release via the endosomal/lysosomal two-pore channels (TPCs). It has been proposed that Tet inhibits the activity of TPCs directly, despite a lack of direct evidence. Using a synthetic, alkynyl diazirine derivative of Tet (AD-Tet), a clickable photoaffinity probe as a tool for target identification, we present results from pulldown SILAC-MS, transcriptomics, biochemical and cell analysis to show that Tet/AD-Tet specifically targets lysosomal integral membrane protein-2 (LIMP-2), a lysosomal cholesterol transporter. Accordingly, we delineated the principles underlying the autophagic and cytotoxic properties of Tet, and discovered that hypercholesteremia is a previously unknown side-effect of Tet in vivo. More importantly, we discover that LIMP-2 is an essential regulator of NAADP-mediated calcium release, and implies that LIMP-2 is a novel target for the development of anti-Ebola virus therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212648 | GEO | 2023/03/04

REPOSITORIES: GEO

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Tetrandrine is a novel inhibitor of NAADP-induced calcium release through targeting Lysosomal Integral Membrane Protein 2 (LIMP-2)

Project description:Tetrandrine is a novel inhibitor of NAADP-induced calcium release through targeting Lysosomal Integral Membrane Protein 2 (LIMP-2)

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Making a predictive heart failure expression profile in Ren2 rat left ventricles

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Lysosomal dysfunction in Down syndrome is APP-dependent and mediated by APP-βCTF (C99)

Project description:Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer’s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down Syndrome (Trisomy 21) requires the extra gene copy of amyloid precursor protein (APP) and is mediated by the beta cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with Down Syndrome (DS), lysosomal degradation of autophagic and endocytic substrates is selectively impaired causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) associated with slowed LC3 turnover and the inactivation of cathepsin D (CTSD) and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, implicating pH elevation as their primary basis. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one BACE1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.

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