三四脯氨酸
免疫系统
结核分枝杆菌
细胞内
生物
先天免疫系统
微生物学
磷酸化
巨噬细胞
PI3K/AKT/mTOR通路
细胞生物学
化学
免疫学
核糖核酸
肺结核
信号转导
RNA结合蛋白
生物化学
医学
基因
病理
体外
作者
Jiawei Wei,Huan Ning,Octavio Ramos‐Espinosa,Christopher S. Eickhoff,Rong Hou,Sheng Wang,Mingui Fu,Ethan Y. Liu,Daping Fan,Daniel F. Hoft,Jianguo Liu
标识
DOI:10.1096/fba.2024-00022
摘要
Abstract Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA‐binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG‐132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF‐α/IL‐12/IL‐23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF‐α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA‐binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host‐directed therapy against tuberculosis (TB).
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