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

Author(s)

Zhang, Min ^{[1, 2]} ; Mishra, Satish ^[3] ; Sakthivel, Ramanavelan ^[4] ; Fontoura, Beatriz M. A. ^[4] ; Nussenzweig, Victor ^[1]

Affiliation

^[1] NYU, Sch Med, Dept Pathol, New York, NY - USA

^[2] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, HIV & Malaria Vaccine Program, 1230 York Ave, New York, NY 10021 - USA

^[3] Cent Drug Res Inst, CSIR, Div Parasitol, Lucknow 226001, Uttar Pradesh - India

^[4] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 - USA

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 12, n. 1 JAN 2016.
• Web of Science Citations: 11

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 alpha (eIF2 alpha). De-phosphorylation of eIF2 alpha-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2 alpha-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 alpha-P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2 alpha 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 alpha, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection. (AU)

• FAPESP's process: 12/50399-4 - Characterization of the protein phosphatase uis2 of Plasmodium as a new tool for malaria drug development
• Grantee: Victor Nussenzweig
• Support Opportunities: Research Projects - SPEC Program