title: 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 2α (eIF2α). De-phosphorylation of eIF2α-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2α-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 eIF2α-P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2α 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 eIF2α, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America.|HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, New York, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: Satish
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Ramanavelan
authors.initials: R
authors.lastname: Sakthivel
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Beatriz M A
authors.initials: BM
authors.lastname: Fontoura
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D055786:Gene Knockout Techniques; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008018:Life Cycle Stages; D008288:Malaria / Q000469:parasitology*; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D010962:Plasmodium berghei / Q000201:enzymology* / Q000254:growth & development*; D034101:Sporozoites / Q000201:enzymology* / Q000254:growth & development*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D010744:Phosphoric Monoester Hydrolases