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ABSTRACT: Stephania tetrandra S. Moore

PROVIDER: PRJNA726521 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14369617.fastq.gz	Fastqsanger.gz
	SRR14369618.fastq.gz	Fastqsanger.gz
	SRR14369619.fastq.gz	Fastqsanger.gz
	SRR14369620.fastq.gz	Fastqsanger.gz
	SRR14369621.fastq.gz	Fastqsanger.gz

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Project description: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.

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