The Journal of Experimental Medicine
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doi:10.1084/jem.20091703
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© Yamamoto et al.
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Article

 A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3

Masahiro Yamamoto1,3, Daron M. Standley4, Seiji Takashima2, Hiroyuki Saiga1,3, Megumi Okuyama1,3, Hisako Kayama1,3, Emi Kubo1, Hiroshi Ito1, Mutsumi Takaura1, Tadashi Matsuda5, Dominique Soldati-Favre6, and Kiyoshi Takeda1,3

1 Department of Microbiology and Immunology and 2 Department of Cardiovascular Medicine, Graduate School of Medicine, and 3 Laboratory of Mucosal Immunology and 4 Laboratory of Systems Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
5 Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
6 Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, University of Geneva, 1211 Geneva 4, Switzerland

CORRESPONDENCE Kiyoshi Takeda: ktakeda{at}ongene.med.osaka-u.ac.jp

Infection by Toxoplasma gondii down-regulates the host innate immune responses, such as proinflammatory cytokine production, in a Stat3-dependent manner. A forward genetic approach recently demonstrated that the type II strain fails to suppress immune responses because of a potential defect in a highly polymorphic parasite-derived kinase, ROP16. We generated ROP16-deficient type I parasites by reverse genetics and found a severe defect in parasite-induced Stat3 activation, culminating in enhanced production of interleukin (IL) 6 and IL-12 p40 in the infected macrophages. Furthermore, overexpression of ROP16 but not ROP18 in mammalian cells resulted in Stat3 phosphorylation and strong activation of Stat3-dependent promoters. In addition, kinase-inactive ROP16 failed to activate Stat3. Comparison of type I and type II ROP16 revealed that a single amino acid substitution in the kinase domain determined the strain difference in terms of Stat3 activation. Moreover, ROP16 bound Stat3 and directly induced phosphorylation of this transcription factor. These results formally establish an essential and direct requirement of ROP16 in parasite-induced Stat3 activation and the significance of a single amino acid replacement in the function of type II ROP16.

Abbreviations used: MEF, mouse embryonic fibroblast; MPA, mycophenolic acid; NLS, nuclear localization signal; TLR, toll-like receptor; YFP, yellow fluorescent protein.

© 2009 Yamamoto et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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