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

Author:

Yamamoto Masahiro11,Standley Daron M.1,Takashima Seiji1,Saiga Hiroyuki11,Okuyama Megumi11,Kayama Hisako11,Kubo Emi1,Ito Hiroshi1,Takaura Mutsumi1,Matsuda Tadashi2,Soldati-Favre Dominique3,Takeda Kiyoshi11

Affiliation:

1. Department of Microbiology and Immunology and Department of Cardiovascular Medicine, Graduate School of Medicine, and Laboratory of Mucosal Immunology and Laboratory of Systems Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

2. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan

3. Department of Microbiology and Molecular Medicine, Centre Médical Universitaire, University of Geneva, 1211 Geneva 4, Switzerland

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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