Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma

Sebastian Lourido, Joel Shuman, Chao Zhang, Kevan M. Shokat, Raymond Hui & L. David Sibley. 2010. Nature.465(7296):359-62.

Student: Yung-Han Yang (楊詠涵)                        Time:14: 00~15:00 Dec. 15, 2010

Commentator: Dr. Chih-Li Hsu (胥直利老師)     Place: Room 601

Abstract

Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge. Although protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Calcium levels have long been associated with Toxoplasma gondii’s interrelated processes of invasion, gliding motility and secretion .T.gondii calcium-dependent protein kinases (TgCDPKs) are attractive targets because they are absent inmammals.The protozoan parasite T. gondii is responsible for widespread infections, is the cause of toxoplasmosis, and lead an obligate intracellular lifestyle, which is critically dependent on the parasite’s ability to invade a suitable vertebrate host cell. The authors used conditional suppression ofTgCDPK1 to reveal that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chemical biology approach in whichpyrazolopyrimidine-derived compounds specifically inhibited TgCDPK1 and disrupted the parasite’s life cycle at stages dependent on microneme secretion. Here the authors show that the TgCDPK1 is an essential regulator of calcium dependent exocytosis in this opportunistic human pathogen, and the potential lead pyrazolopyrimidine-derived compounds for the development of specific anti-parasitic drugs.

References

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