Wu Xiaoling, Zhang Jiamei, Ma Chenjie, Li Wu, Zeng Jin, Wang Yujiong, Deng Guangcun
Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Yinchuan, 750021, Ningxia, China; College of Life Science, Ningxia University, Yinchuan, 750021, Ningxia, China.
Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China, Yinchuan, 750021, Ningxia, China; College of Life Science, Ningxia University, Yinchuan, 750021, Ningxia, China.
Microb Pathog. 2019 Feb;127:277-287. doi: 10.1016/j.micpath.2018.12.016. Epub 2018 Dec 11.
Mycobacterium tuberculosis (Mtb)-induced autophagy of alveolar macrophages has been confirmed to play a central role in the pathogenesis of tuberculosis. Growing evidence indicates that excessive or uncontrolled autophagic activity, which results in type II programmed cell death, can be regulated by many factors, including Wnt/β-catenin signalling. Wnt/β-catenin signalling has been demonstrated to be involved in multiple diseases through the regulation of autophagy; however, its exact role in regulating autophagy induced by Mtb remains unclear. Accordingly, this study examined the function of the Wnt/β-catenin signalling pathway in regulating Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-induced autophagy in RAW264.7 macrophage cell line. In the present study, we found that BCG induced the autophagy of RAW264.7 cells in a time- and dose-dependent manner along with an accumulation of LC3 (Microtubule-associated protein 1 light chain 3) protein. Intriguingly, Wnt3a, a Wnt/β-catenin signalling ligand, significantly inhibited autophagy, with decreased autophagy rates and autophagic flux. An immunoblot analysis further revealed that Wnt/β-catenin signalling was capable of inhibiting the expression of the LC3 and autophagy-associated gene (Atg) cascade proteins in BCG-infected cells. Mechanistically, Wnt/β-catenin signalling may inhibit autophagy in BCG-infected macrophages by activating mTOR-dependent pathways. Our findings reveal the mechanisms of Wnt/β-catenin signalling regulates cellular autophagy induced by Mtb and provide novel insights into physiological and immune control of tuberculosis by modulating autophagy processes.
结核分枝杆菌（Mtb）诱导的肺泡巨噬细胞自噬已被证实在结核病发病机制中起核心作用。越来越多的证据表明，导致II型程序性细胞死亡的过度或不受控制的自噬活性可受多种因素调节，包括Wnt/β-连环蛋白信号通路。Wnt/β-连环蛋白信号通路已被证明通过自噬调节参与多种疾病；然而，其在调节Mtb诱导的自噬中的确切作用仍不清楚。因此，本研究检测了Wnt/β-连环蛋白信号通路在调节牛分枝杆菌卡介苗（BCG）诱导的RAW264.7巨噬细胞系自噬中的功能。在本研究中，我们发现BCG以时间和剂量依赖性方式诱导RAW264.7细胞自噬，同时伴有微管相关蛋白1轻链3（LC3）蛋白的积累。有趣的是，Wnt/β-连环蛋白信号配体Wnt3a显著抑制自噬，自噬率和自噬通量降低。免疫印迹分析进一步显示，Wnt/β-连环蛋白信号通路能够抑制BCG感染细胞中LC3和自噬相关基因（Atg）级联蛋白的表达。机制上，Wnt/β-连环蛋白信号通路可能通过激活mTOR依赖性途径抑制BCG感染巨噬细胞中的自噬。我们的研究结果揭示了Wnt/β-连环蛋白信号通路调节Mtb诱导的细胞自噬的机制，并通过调节自噬过程为结核病的生理和免疫控制提供了新的见解。
