Inhibition of ATF6β-dependent host adaptive immune response by a Toxoplasma virulence factor ROP18

Abstract

Toxoplasma gondii (T. gondii) secretes various effector molecules, which co-opt host cells and enable parasite proliferation. Of these, the rhoptry protein, ROP18, is a parasite-derived factor that determines acute virulence. ROP18 is injected into the host cytoplasm during infection and, eventually, localizes to parasitophorous vacuole (PV) membranes. ROP18 is predicted to be a serine/threonine kinase; however, the molecular mechanism by which ROP18 mediates its pathological effects remains unclear. At the end of 2010, two groups reported that ROP18 targets and phosphorylates interferon-inducible p47 small GTPases (IRGs), demonstrating the parasite’s strategy for disarming the innate defense system. Recently, we described a mechanism by which ROP18 mediates degradation of the host endoplasmic reticulum-localizing transcription factor, ATF6β, to downregulate CD8 T cell-mediated type I adaptive immune responses. Taken together, these results suggest that T. gondii inactivates host innate and adaptive immune responses by targeting different host immunity-related molecules: IRGs and ATF6β.

Keywords: :

• ATF6β
• IRGs
• effector molecules
• virulence

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Acknowledgments

We thank C. Hidaka and M. Yasuda for excellent secretarial assistance; Y. Magota for technical assistance; and members of Takeda’s lab for discussions. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, the Strategic International Cooperative Program (Research Exchange Type), the Japan Science and Technology Agency (JST), and the Takeda Science Foundation; KANAE FOUNDATION FOR THE PROMOTION OF MEDICAL SCIENCE; The Cell Science Research Foundation; THE ICHIRO KANEHARA FOUNDATION; Kato Memorial Bioscience Foundation; THE UEHARA MEMORIAL FOUNDATION; and Mochida Memorial Foundation for Medical and Pharmaceutical Research.