2013 Fiscal Year Annual Research Report
トキソプラズマ原虫分泌蛋白質（ＰＳＰ＃７）の病原性における役割の解析
| Project/Area Number |
13J01218
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| Research Institution | Osaka University |
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Principal Investigator |
馬 知秀 大阪大学, 医学系研究科, 特別研究員(DC2)
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| Keywords | Toxoplasma gondii / NFAT4 / Calcineurin / CAMLG |
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| Research Abstract |
Infection by Toxoplasma gondii results in co-option and subversion of host cellular signaling pathways. The takeover process is operated by T. gondii effector molecules secreted from parasite organelles such as rhoptries and dense granules. I found previously that overexpression of PSP#7 strongly up-regulate the NFAT dependent promoter activities and involved in parasite virulence in mice. Last year, I have investigated the molecular mechanism by which PSP#7 mediated activation of the host transcription factors NFAT.
1) T. gondii secreted protein PSP#7 critically regulates the activation of the host transcription factor NFAT4. Overexpression of PSP#7 results in robust activation of the NFAT-dependent promoter in a calcineurin-dependent manner. The C-terminus of PSP#7 associates with an NFAT activating signaling molecule CAMLG and the dominant negative or silencing of CAMLG down-regulate the PSP#7- mediated NFAT activation. Furthermore, the PSP#7-CAMLG axis selectively activates NFAT4 in mammalian cells. Indeed, infection of wild-type, but not PSP#7-deficient, parasites induces nuclear translocation of NFAT4. Taken together, these results implicated PSP#7 in the CAMLG-dependent selective activation of NFAT4 in mammalian cells.
2) Polymorphisms on PSP#7 determine strain-dependent NFAT4 activation. Infection with type Iparasites culminated in significantly higher NFAT4 activation than did type II parasite infection. Comparison of type I and type II PSP#7 revealed that a single amino acid substitution and deletions in the C-terminus account for this difference. These results demonstrate that T. gondii PSP#7 plays an important role in NFAT4 activation in a strain-dependent manner.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
I demonstrate that PSP#7 triggers the host signaling pathway for activation of a host transcription factor NFAT4, and that a polymorphism in the C-terminus of PSP#7 is associated with strain-specific NFAT4 activation. I have achieved the goals of the first year.
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| Strategy for Future Research Activity |
This year, I will investigate the role of PSP#7 in in vivo virulence in mice.
1) Analysis of parasite virulence in NFAT4-deficient mice.
2) Significance of NFAT4 activation in influencing parasite virulence.
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Research Products
(2 results)
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[Journal Article] Role of Mouse and Human Autophagy Proteins in IFN-γ-Induced Cell-Autonomous Responses against Thxoplasma gondii2014
Author(s)
Jun Ohshima, Youngae Lee, Miwa Sasai, Tatsuya Saitoh, Ji Su Ma, Naganori Kamiyama, Yoshiharu Matsuura, Suh Pann-Ghill, Mikako Hayashi, Shigeyuki Ebisu, Kiyoshi Takeda, Shizuo Akira, and Masahiro Yamamoto.
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Journal Title
The Journal of Immunology
Volume: 192(7)
Pages: 3328-35
DOI
Peer Reviewed
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