Hu Dong, Wu Jing, Wang Wan, Mu Min, Zhao Runpeng, Xu Xuewei, Chen Zhaoquan, Xiao Jian, Hu Fengyu, Yang Yabo, Zhang Rongbo
Institute of Infection and Immunology, Department of Medical Immunology, Medical School, Anhui University of Science and Technology, Huainan, China.
Institute of Infection and Immunology, Department of Medical Immunology, Medical School, Anhui University of Science and Technology, Huainan, China.
Biochem Biophys Res Commun. 2015 May 29;461(2):401-7. doi: 10.1016/j.bbrc.2015.04.051. Epub 2015 Apr 18.
The mechanism underlying autophagy alteration by mycobacterium tuberculosis remains unclear. Our previous study shows LpqH, a lipoprotein of mycobacterium tuberculosis, can cause autophagosomes accumulation in murine macrophages. It is well known that SapM, another virulence factor, plays an important role in blocking phagosome-endosome fusion. However, the mechanism that SapM interferes with autophagy remains poorly defined. In this study, we report that SapM suppresses the autophagy flux by blocking autophagosome fusion with lysosome. Exposure to SapM results in accumulations of autophagosomes and decreased co-localization of autophagosome with lysosome. Molecularly, Rab7, a small GTPase, is blocked by SapM through its CT domain and is prevented from involvement of autophagosome-lysosome fusion. In conclusion, our study reveals that SapM takes Rab7 as a previously unknown target to govern a distinct molecular mechanism underlying autophagosome-lysosome fusion, which may bring light to a new thought about developing potential drugs or vaccines against tuberculosis.
结核分枝杆菌引起自噬改变的潜在机制仍不清楚。我们之前的研究表明，结核分枝杆菌的脂蛋白LpqH可导致小鼠巨噬细胞中自噬体积累。众所周知，另一种毒力因子SapM在阻断吞噬体-内体融合中起重要作用。然而，SapM干扰自噬的机制仍不清楚。在本研究中，我们报告SapM通过阻断自噬体与溶酶体的融合来抑制自噬流。暴露于SapM会导致自噬体积累，并减少自噬体与溶酶体的共定位。在分子水平上，小GTP酶Rab7被SapM通过其CT结构域阻断，从而无法参与自噬体-溶酶体融合。总之，我们的研究表明，SapM将Rab7作为一个此前未知的靶点，来调控自噬体-溶酶体融合的独特分子机制，这可能为开发抗结核潜在药物或疫苗带来新的思路。
