2. Academic Validation
  3. 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

  • Adv Sci (Weinh). 2024 Jun 21:e2400952. doi: 10.1002/advs.202400952.
Zhiqiang Hu 1 2,  Yufen Zhang 1,  Yingchao Xie 1,  Jianwu Yang 1,  Haotian Tang 3,  Bolin Fan 4,  Ke Zeng 1,  Zhongxin Han 1,  Jiansen Lu 1 5,  Huaji Jiang 1 6,  Wenqiang Peng 1,  Hongyu Li 1,  Huadan Chen 1,  Sha Wu 1 7,  Bang Shen 4,  Zhao-Rong Lun 3,  Xiao Yu 1 8
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 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.
  • 3 State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
  • 4 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
  • 5 Department of Joint Surgery, the Fifth Affiliated Hospital of Southern Medical University, Guangzhou, 510900, China.
  • 6 Yue Bei People's Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, 510515, China.
  • 7 Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, 510515, China.
  • 8 Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China.
PMID: 39031880 DOI: 10.1002/advs.202400952
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.

Keywords

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

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