ATF6 beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18

作者：Yamamoto Masahiro; Ma Ji Su; Mueller Christina; Kamiyama Naganori; Saiga Hiroyuki; Kubo Emi; Kimura Taishi; Okamoto Toru; Okuyama Megumi; Kayama Hisako; Nagamune Kisaburo; Takashima Seiji; Matsuura Yoshiharu; Soldati Favre Dominique; Takeda Kiyoshi^*

来源：Journal of Experimental Medicine, 2011, 208(7): 1533-1546.

DOI：10.1084/jem.20101660

The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum-bound transcription factor ATF6 beta. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6 beta-dependent pathogenicity by interacting with ATF6 beta and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6 beta and for parasite virulence. Consistent with a key role for ATF6 beta in resistance against this intracellular pathogen, ATF6 beta-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6 beta-dependent immune responses is a novel pathogenic mechanism induced by ROP18.

• 出版日期2011-7-4