期刊
EMBO REPORTS
卷 23, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/embr.202154022
关键词
CDPK; kinase; malaria; phospholipids; phosphoproteomics; signaling
资金
- Department of Biotechnology [BT/COE/34/SP15138/2015, BT/PR7976/BRB/10/1223/2013]
- Department of Science and Technology, India [SB/SO/BB/006/2014]
- NII core
- J.C. Bose Fellowship
- CSIR
- UGC
- Agence Nationale pour la Recherche, France [ANR-12-PDOC-0028, ANR-21-CE44-0010-01]
- Fondation pour la Recherche Medicale (FRM) [EQU202102012700]
- Finovi programs
- Laboratoire d' Excellence Parafrap, France [ANR-11-LABX-0024]
- Region Auvergne Rhone Alpes (IRICE)
- Yenepoya
- Ministry of Health and Family Welfare, Government of India
- Agence Nationale de la Recherche (ANR) [ANR-12-PDOC-0028, ANR-21-CE44-0010] Funding Source: Agence Nationale de la Recherche (ANR)
The study reveals that PfCDPK7 promotes phosphatidylcholine synthesis by regulating key enzymes involved in the process and interacts with 4'-phosphorylated phosphoinositides generated by PI4-kinase. Inhibition of PI4K disrupts the vesicular localization of PfCDPK7. Inhibitors of PfPI4K may control phospholipid biosynthesis through regulation of PfCDPK7 localization and activity.
PfCDPK7 is an atypical member of the calcium-dependent protein kinase (CDPK) family and is crucial for the development of Plasmodium falciparum. However, the mechanisms whereby PfCDPK7 regulates parasite development remain unknown. Here, we perform quantitative phosphoproteomics and phospholipid analysis and find that PfCDPK7 promotes phosphatidylcholine (PC) synthesis by regulating two key enzymes involved in PC synthesis, phosphoethanolamine-N-methyltransferase (PMT) and ethanolamine kinase (EK). In the absence of PfCDPK7, both enzymes are hypophosphorylated and PMT is degraded. We further find that PfCDPK7 interacts with 4'-phosphorylated phosphoinositides (PIPs) generated by PI4-kinase. Inhibition of PI4K activity disrupts the vesicular localization PfCDPK7. P. falciparum PI4-kinase, PfPI4K is a prominent drug target and one of its inhibitors, MMV39048, has reached Phase I clinical trials. Using this inhibitor, we demonstrate that PfPI4K controls phospholipid biosynthesis and may act in part by regulating PfCDPK7 localization and activity. These studies not only unravel a signaling pathway involving PfPI4K/4'-PIPs and PfCDPK7 but also provide novel insights into the mechanism of action of a promising series of candidate anti-malarial drugs.
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