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journal article·2024-08Open access

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

Advanced Science· Volume 11· Issue 32
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Source abstract

Abstract

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 Δgra4 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 autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN‐I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR‐1+CD11b+ dendritic cell subset, thereby enhancing T cell anti‐tumor 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.
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Research context

Catalysis & surfaces

OpenAlex topics: Toxoplasma gondii Research Studies · Autophagy in Disease and Therapy · interferon and immune responses

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine Zhejiang University School of Medicine Zhejiang University Hangzhou 310029 China

State Key Laboratory of Biocontrol, School of Life Sciences Sun Yat‐sen University Guangzhou 510275 China

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine Huazhong Agricultural University Wuhan 430070 China

Department of Joint Surgery the Fifth Affiliated Hospital of Southern Medical University Guangzhou 510900 China

Yue Bei People's Hospital Postdoctoral Innovation Practice Base Southern Medical University Guangzhou 510515 China

Guangdong Provincial Key Laboratory of Proteomics Southern Medical University Guangzhou 510515 China

Department of Clinical Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510000 China

Funding

National Natural Science Foundation of China · Postdoctoral Research Foundation of China · Basic and Applied Basic Research Foundation of Guangdong Province

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