The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress
The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress
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DOI：
10.1074/jbc.m110.135251
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Balaji, Kithiganahalli N.
中科院分区：
文献类型：
--
作者：
Chaturvedi, Rashmi;Bansal, Kushagra;Balaji, Kithiganahalli N.
结核分枝杆菌利用独特的策略在受感染宿主细胞的恶劣环境中生存。一种独特的分枝杆菌细胞表面抗原的特异性表达可以调节关键的信号级联反应，可以作为一个关键的生存策略，减少宿主效应反应，如氧化应激。我们在这里证明，假设PE_PGRS11 ORF编码一个功能性磷酸甘油酸酯酶。转录分析显示PE_PGRS11是一个低氧应答基因，通过重组腺病毒或耻垢分枝杆菌增强PE_PGRS11的表达可使肺泡上皮细胞抵抗氧化应激。PE_PGRS 11诱导的对氧化应激的抗性需要调节遗传标记，如诱导Bcl 2或考克斯-2的表达。这种特异性抗凋亡分子特征的调节涉及TLR 2对PE_PGRS 11的识别和随后PI 3 K-ERK 1/ 2-NF-κ B信号传导轴的激活。此外，PE_PGRS11显著降低H2 O2诱导的p38 MAPK激活。有趣的是，PE_PGRS11蛋白暴露在分枝杆菌细胞表面，并参与氧化应激下分枝杆菌的存活。此外，PE_PGRS 11在结核病感染期间显示出不同的B细胞应答。综上所述，我们的研究确定PE_PGRS 11作为体内表达的免疫显性抗原，其通过触发考克斯-2和Bcl 2的TLR 2依赖性表达在调节氧化应激期间施加的细胞寿命限制中起关键作用。这些观察结果清楚地提供了一个机制的基础，从氧化应激的致病性分枝杆菌感染的肺上皮细胞的救援。
Mycobacterium tuberculosis utilizes unique strategies to survive amid the hostile environment of infected host cells. Infection-specific expression of a unique mycobacterial cell surface antigen that could modulate key signaling cascades can act as a key survival strategy in curtailing host effector responses like oxidative stress. We demonstrate here that hypothetical PE_PGRS11 ORF encodes a functional phosphoglycerate mutase. The transcriptional analysis revealed that PE_PGRS11 is a hypoxia-responsive gene, and enforced expression of PE_PGRS11 by recombinant adenovirus or Mycobacterium smegmatis imparted resistance to alveolar epithelial cells against oxidative stress. PE_PGRS11-induced resistance to oxidative stress necessitated the modulation of genetic signatures like induced expression of Bcl2 or COX-2. This modulation of specific antiapoptotic molecular signatures involved recognition of PE_PGRS11 by TLR2 and subsequent activation of the PI3K-ERK1/ 2-NF-kappa B signaling axis. Furthermore, PE_PGRS11 markedly diminished H2O2-induced p38 MAPK activation. Interestingly, PE_PGRS11 protein was exposed at the mycobacterial cell surface and was involved in survival of mycobacteria under oxidative stress. Furthermore, PE_PGRS11 displayed differential B cell responses during tuberculosis infection. Taken together, our investigation identified PE_PGRS11 as an in vivo expressed immunodominant antigen that plays a crucial role in modulating cellular life span restrictions imposed during oxidative stress by triggering TLR2-dependent expression of COX-2 and Bcl2. These observations clearly provide a mechanistic basis for the rescue of pathogenic Mycobacterium-infected lung epithelial cells from oxidative stress.