UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages.

ABSTRACT: Plasmodium salivary sporozoites are the infectious form of the malaria parasite and are dormant inside salivary glands of Anopheles mosquitoes. During dormancy, protein translation is inhibited by the kinase UIS1 that phosphorylates serine 59 in the eukaryotic initiation factor 2? (eIF2?). De-phosphorylation of eIF2?-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2?-P is mediated by the protein phosphatase 1 (PP1). Using a series of genetically knockout parasites we showed that in malaria sporozoites, contrary to mammalian cells, the eIF2?-P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2? was highly phosphorylated in uis2 conditional knockout sporozoites. These mutant sporozoites maintained the crescent shape after delivery into mammalian host and lost their infectivity. Both uis1 and uis2 were highly transcribed in the salivary gland sporozoites but uis2 expression was inhibited by the Pumilio protein Puf2. The repression of uis2 expression was alleviated when sporozoites developed into liver stage. While most eukaryotic phosphatases interact transiently with their substrates, UIS2 stably bound to phosphorylated eIF2?, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC4712141 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature