1. Coxiella burnetii effector CvpE maintains biogenesis of Coxiella -containing vacuoles by suppressing lysosome tubulation through binding PI(3)P and perturbing PIKfyve activity on lysosomes.
- Author
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Zhao M, Zhang S, Wan W, Zhou C, Li N, Cheng R, Yu Y, Ouyang X, Zhou D, Jiao J, and Xiong X
- Subjects
- Animals, Humans, HeLa Cells, Host-Pathogen Interactions, Q Fever microbiology, Bacterial Proteins metabolism, Bacterial Proteins genetics, Coxiella burnetii metabolism, Coxiella burnetii growth & development, Coxiella burnetii genetics, Lysosomes metabolism, Lysosomes microbiology, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol Phosphates metabolism, Transient Receptor Potential Channels metabolism, Transient Receptor Potential Channels genetics, Vacuoles microbiology, Vacuoles metabolism
- Abstract
Coxiella burnetii ( C. burnetii ) is the causative agent of Q fever, a zoonotic disease. Intracellular replication of C. burnetii requires the maturation of a phagolysosome-like compartment known as the replication permissive Coxiella -containing vacuole (CCV). Effector proteins secreted by the Dot/Icm secretion system are indispensable for maturation of a single large CCV by facilitating the fusion of promiscuous vesicles. However, the mechanisms of CCV maintenance and evasion of host cell clearance remain to be defined. Here, we show that C. burnetii secreted Coxiella vacuolar protein E (CvpE) contributes to CCV biogenesis by inducing lysosome-like vacuole (LLV) enlargement. LLV fission by tubulation and autolysosome degradation is impaired in CvpE-expressing cells. Subsequently, we found that CvpE suppresses lysosomal Ca
2+ channel transient receptor potential channel mucolipin 1 (TRPML1) activity in an indirect manner, in which CvpE binds phosphatidylinositol 3-phosphate [PI(3)P] and perturbs PIKfyve activity in lysosomes. Finally, the agonist of TRPML1, ML-SA5, inhibits CCV biogenesis and C. burnetii replication. These results provide insight into the mechanisms of CCV maintenance by CvpE and suggest that the agonist of TRPML1 can be a novel potential treatment that does not rely on antibiotics for Q fever by enhancing Coxiella-containing vacuoles (CCVs) fission.- Published
- 2024
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