Duan Liang, Yi Min, Chen Juan, Li Shengjin, Chen Weixian
Department of Laboratory Medicine, The Second Hospital Affiliated to Chongqing Medical University, Chongqing, 400010, China.
Department of Respiratory, The Second Hospital Affiliated to Chongqing Medical University, Chongqing, 400010, China.
Biochem Biophys Res Commun. 2016 May 13;473(4):1229-1234. doi: 10.1016/j.bbrc.2016.04.045. Epub 2016 Apr 11.
Autophagy plays a crucial role in the progress of Mycobacterium tuberculosis (MTB) infection. Recently, MTB enhanced intracellular survival (EIS) protein was reported to be secreted from MTB cells and linked to the inhibition of autophagy and the intracellular persistence of the pathogen. Here, we investigated the mechanism of EIS-mediated inhibition of autophagy in a human phorbol myristate acetate (PMA)-treated THP-1 cell line as well as in murine macrophages. We confirmed that the presence of EIS led to the inhibition of rapamycin (Rapa)-induced autophagy, while IL-10 gene expression was increased and Akt/mTOR/p70S6K pathway was activated during the process. IL-10 gene silencing led to a significant recovery of EIS-mediated autophagy suppression and decreased activity of the Akt/mTOR/p70S6K pathway. IL-10 promoter activity was unaffected by EIS. Remarkably, EIS increased the acetylation level of histone H3 (Ac-H3), which binds to the SP1 and STAT3 region of the human IL-10 gene promoter sequence. Thus, EIS protein possibly increased IL-10 expression through the regulation of Ac-H3 of its promoter. Our data demonstrated that one possible mechanism of the MTB evasion of autophagy is that the EIS protein up-regulates IL-10 via Ac-H3 and thus activates Akt/mTOR/p70S6K pathway.
自噬在结核分枝杆菌（MTB）感染进程中发挥着关键作用。最近，有报道称MTB增强胞内存活（EIS）蛋白是从MTB细胞分泌的，并且与自噬抑制及该病原体的胞内持续存在有关。在此，我们研究了EIS介导的自噬抑制在人佛波酯肉豆蔻酸酯（PMA）处理的THP-1细胞系以及小鼠巨噬细胞中的机制。我们证实EIS的存在导致雷帕霉素（Rapa）诱导的自噬受到抑制，而在此过程中白细胞介素-10（IL-10）基因表达增加且Akt/mTOR/p70S6K通路被激活。IL-10基因沉默导致EIS介导的自噬抑制显著恢复，且Akt/mTOR/p70S6K通路活性降低。EIS对IL-10启动子活性无影响。值得注意的是，EIS增加了组蛋白H3（Ac-H3）的乙酰化水平，其与人IL-10基因启动子序列的SP1和信号转导子与转录激活子3（STAT3）区域结合。因此，EIS蛋白可能通过调控其启动子的Ac-H3来增加IL-10表达。我们的数据表明MTB逃避自噬的一种可能机制是EIS蛋白通过Ac-H3上调IL-10，从而激活Akt/mTOR/p70S6K通路。
