Conformational Switch Driven Membrane Pore Formation by Mycobacterium Secretory Protein MPT63 Induces Macrophage Cell Death.,ACS Chemical Biology

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Conformational Switch Driven Membrane Pore Formation by Mycobacterium Secretory Protein MPT63 Induces Macrophage Cell Death.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-07-08 , DOI: 10.1021/acschembio.9b00327
Achinta Sannigrahi ₁ , Indrani Nandi _{1,

2} , Sayantani Chall ₁ , Junaid Jibran Jawed ₃ , Animesh Halder ₄ , Subrata Majumdar ₃ , Sanat Karmakar ₄ , Krishnananda Chattopadhyay _{1,

2}

Affiliation

Virulent Mycobacterium tuberculosis (MTB) strains cause cell death of macrophages (Mϕ) inside TB granuloma using a mechanism which is not well understood. Many bacterial systems utilize toxins to induce host cell damage, which occurs along with immune evasion. These toxins often use chameleon sequences to generate an environment-sensitive conformational switch, facilitating the process of infection. The presence of toxins is not yet known for MTB. Here, we show that MTB-secreted immunogenic MPT63 protein undergoes a switch from β-sheet to helix in response to mutational and environmental stresses. MPT63 in its helical form creates pores in both synthetic and Mϕ membranes, while the native β-sheet protein remains inert toward membrane interactions. Using fluorescence correlation spectroscopy and atomic force microscopy, we show further that the helical form undergoes self-association to produce toxic oligomers of different morphology. Trypan blue and flow cytometry analyses reveal that the helical state can be utilized by MTB for killing Mϕ cells. Collectively, our study emphasizes for the first time a toxin-like behavior of MPT63 induced by an environment-dependent conformational switch, resulting in membrane pore formation by toxic oligomers and Mϕ cell death.

中文翻译：

分枝杆菌分泌蛋白MPT63构象开关驱动的膜孔形成诱导巨噬细胞死亡。

致病性结核分枝杆菌（MTB）菌株使用尚未充分了解的机制引起结核性肉芽肿内巨噬细胞（Mϕ）的细胞死亡。许多细菌系统利用毒素来诱导宿主细胞损伤，这种损伤与免疫逃逸一起发生。这些毒素通常使用变色龙序列来产生对环境敏感的构象转换，从而促进感染过程。毒素的存在尚未为MTB所知。在这里，我们显示了MTB分泌的免疫原性MPT63蛋白响应突变和环境胁迫而经历了从β-折叠到螺旋的转换。呈螺旋形式的MPT63在合成膜和Mϕ膜上均形成孔，而天然β-折叠蛋白对膜相互作用保持惰性。使用荧光相关光谱和原子力显微镜，我们进一步表明，螺旋形式经历了自缔合以产生不同形态的有毒低聚物。台盼蓝和流式细胞仪分析表明，MTB可以利用螺旋状态杀死Mϕ细胞。总的来说，我们的研究首次强调了由环境依赖性构象转换引起的MPT63的类毒素行为，其由有毒的低聚物形成膜孔并导致M death细胞死亡。

更新日期：2019-06-26

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