Journal
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
Volume 5, Issue 1, Pages 1-8Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2014.12.001
Keywords
Cytokinesis; BKI; MAPK; Toxoplastria gondii
Categories
Funding
- JSPS Research Fellowship for Young Scientists
- Ministry of Education, Culture, Science, Sports, and Technology (MEXT) of Japan
- Program for the Promotion of Basic and Applied Research for Innovations in Bio-oriented Industry (BRAIN)
- Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry
- Program to Disseminate Tenure Tracking System from the Japan Science and Technology Agency (JST)
- Grants-in-Aid for Scientific Research [14J07030, 15H01306] Funding Source: KAKEN
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Toxoplasma gondii is the causative pathogen for Toxoplasmosis. Bumped kinase inhibitor 1NM-PP1 inhibits the growth of T. gondii by targeting TgCDPK1. However, we recently reported that resistance to 1NM-PP1 can be acquired via a mutation in T gouda mitogen-activated protein kinase like 1 (TgMAPKL-1). Further characterization of how this TgMAPKL-1 mutation restores the inhibitory effect of 1NM-PP1 would shed further light on the function of TgMAPKL-1 in the parasite life cycle. Therefore, we made parasite clones with TgMAPKL-1 mutated at the gatekeeper residue Ser 191, which is critical for 1NM-PP1 susceptibility. Host cell lysis of RH/ku80(-)/HA-TgMAPKL-1(S191A) was completely inhibited at 250 nM 1NM-PP1, whereas that of RH/ku80(-)/HA-TgMAPKL-1(S191Y) was not. By comparing 1NM-PP1-sensitive (RH/ku80(-)/HA-TgMAPKL-1(S191A)) and -resistant (RH/ku80(-)/HA-TgMAPKL-1(S191Y)) clones, we observed that inhibition of TgMAPKL-1 blocked cell cycle progression after DNA duplication. Morphological analysis revealed that TgMAPKL-1 inhibition caused enlarged parasite cells with many daughter cell scaffolds and imcomplete cytokinesis. We conclude that the mutation in TgMAPKL-1 restored the cell cycle-arresting effect of 1NM-PP1 on T. gondii endodyogeny. Given that endodyogeny is the primary mechanism of cell division for both the tachyzoite and bradyzoite stages of this parasite, TgMAPKL-1 may be a promising target for drug development. Exploration of the signals that regulate TgMAPKL-1 will provide further insights into the unique mode of T. gondii cell division. (C) 2014 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
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