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Zhiqiang Hu ; ?Yufen Zhang ; ?Yingchao Xie , et al. Adv. Sci.,2024,2400952. DOI: 10.1002/advs.202400952
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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 autophagy 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 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
Purchased from AmBeed: 133407-82-6
CAS No. : | 133407-82-6 | MDL No. : | MFCD00674886 |
Formula : | C26H41N3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TZYWCYJVHRLUCT-VABKMULXSA-N |
M.W : | 475.62 | Pubchem ID : | 462382 |
Synonyms : |
Z-Leu-Leu-Leu-al;Z-Leu-Leu-Leu-CHO;MGI-132;(S)-MG132;MG132 SSS
|
Chemical Name : | Benzyl ((S)-4-methyl-1-(((S)-4-methyl-1-(((S)-4-methyl-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl)amino)-1-oxopentan-2-yl)carbamate |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |