PXD064455

PXD064455 is an original dataset announced via ProteomeXchange.

Title	Tetrandrine regulates NAADP-mediated calcium signalling by a novel LIMP-2-dependent, sphingosine-mediated mechanism
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-06-05
AnnouncementXML	Submission_2025-06-05_04:36:25.078.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ricky Chan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-30 09:09:18	ID requested
⏵ 1	2025-06-05 04:36:25	announced

Dataset with its publication pending

submitter keyword: Tetrandrine

LIMP-2

sphingosine-mediated mechanism

Proteomics

Chi-bun Ko
contact affiliation	The Hong Kong Polytechnic University
contact email	ben.ko@polyu.edu.hk
lab head
Ricky Chan
contact affiliation	The Hong Kong Polytechnic University
contact email	15902803r@connect.polyu.hk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/06/PXD064455

PRIDE project URI

• PRIDE
  1. PXD064455
     1. Label: PRIDE project
     2. Name: Tetrandrine regulates NAADP-mediated calcium signalling by a novel LIMP-2-dependent, sphingosine-mediated mechanism