Products Cited in Publications Worldwide The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti-T. Gondii Immunity and Tumor Immunotherapy

The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti-T. Gondii Immunity and Tumor Immunotherapy

Zhiqiang Hu; Yufen Zhang; Yingchao Xie; Jianwu Yang; Haotian Tang; Bolin Fan; Ke Zeng; Zhongxin Han; Jiansen Lu; Huaji Jiang; Wenqiang Peng; Hongyu Li; Huadan Chen; Sha Wu; Bang Shen; Zhao-Rong Lun; Xiao Yu

DOI:

Abstract

Toxoplasma gondii (T. gondii)-associated polymorphic effector proteins are crucial in parasite development and regulating host anti-T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN-I activation. Infection with ∆gra4 mutant T. gondii strain induces stronger IFN-I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27-catalyzed K48-ubiquitination at Lys251/Lys372 residues, which enhances its recognition by receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent ∆gra4 strain (ME49∆ompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN-I production. Earlier vaccination with ME49∆ompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49∆ompdc treatment. Notably, ME49∆ompdc/gra4 vaccination induces a specific CD64 +MAR-1 +CD11b + dendritic cell subset, thereby enhancing T cell responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN-I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.

Keywords

attenuated T. gondii ; selective autophagy ; toxoplasmosis ; tumor therapy ; type I interferon

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