| 研究概要 |
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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