Plant hormone cytokinins control cell cycle progression and plastid replication in apicomplexan parasites.
Cytokinins are plant hormones that are involved in regulation of cell proliferation, cell cycle progression, and cell and plastid development. Here, we show that the apicomplexan parasites Toxoplasma gondii and Plasmodium berghei, an opportunistic human pathogen and a rodent malaria agent, respectively, produce cytokinins via a biosynthetic pathway similar to that in plants. Cytokinins regulate the growth and cell cycle progression of T. gondii by mediating expression of the cyclin gene TgCYC4. A natural form of cytokinin, trans-zeatin (t-zeatin), upregulated expression of this cyclin, while a synthetic cytokinin, thidiazuron, downregulated its expression. Immunofluorescence microscopy and quantitative PCR analysis showed that t-zeatin increased the genome-copy number of apicoplast, which are non-photosynthetic plastid, in the parasite, while thidiazuron led to their disappearance. Thidiazuron inhibited growth of T. gondii and Plasmodium falciparum, a human malaria parasite, suggesting that thidiazuron has therapeutic potential as an inhibitor of apicomplexan parasites.
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; School of Medicine, Keio University, Tokyo, Japan.
Syed Bilal Ahmad
SBA
Andrabi
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
Michiru
M
Tahara
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
Ryuma
R
Matsubara
Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; Graduate School of Medicine, Osaka University, Osaka, Japan.
Tomoko
T
Toyama
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; Department of Tropical Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Hiroka
H
Aonuma
RIKEN Center for Sustainable Resource Science, Kanagawa, Japan.
Hitoshi
H
Sakakibara
School of Medicine, Keio University, Tokyo, Japan.
Makoto
M
Suematsu
Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Kazuyuki
K
Tanabe
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
Tomoyoshi
T
Nozaki
Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan. Electronic address: nagamune@niid.go.jp.
Kisaburo
K
Nagamune
D002453:Cell Cycle / Q000187:drug effects*; D003583:Cytokinins / Q000378:metabolism / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010937:Plant Growth Regulators / Q000378:metabolism / Q000494:pharmacology; D010962:Plasmodium berghei / Q000201:enzymology* / Q000254:growth & development / Q000502:physiology*; D013830:Thiadiazoles / Q000494:pharmacology; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*
D003583:Cytokinins; D010671:Phenylurea Compounds; D010937:Plant Growth Regulators; D013830:Thiadiazoles; C016785:thidiazuron
Cytokinins; Plant hormones; Plasmodium berghei; Thidiazuron; Toxoplasma gondii