Yang Dong, Klebl David P, Zeng Sheng, Sobott Frank, Prévost Martine, Soumillion Patrice, Vandenbussche Guy, Fontaine Véronique
Microbiology, Bioorganic and Macromolecular Chemistry Unit, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, CP205/2, 1050, Brussels, Belgium.
Metallomics. 2020 Aug 19;12(8):1267-1277. doi: 10.1039/d0mt00101e.
The recalcitrance of pathogenic Mycobacterium tuberculosis, the agent of tuberculosis, to eradication is due to various factors allowing bacteria to escape from stress situations. The mycobacterial chaperone GroEL1, overproduced after macrophage entry and under oxidative stress, could be one of these key players. We previously reported that GroEL1 is necessary for the biosynthesis of phthiocerol dimycocerosate, a virulence-associated lipid and for reducing antibiotic susceptibility. In the present study, we showed that GroEL1, bearing a unique C-terminal histidine-rich region, is required for copper tolerance during Mycobacterium bovis BCG biofilm growth. Mass spectrometry analysis demonstrated that GroEL1 displays high affinity for copper ions, especially at its C-terminal histidine-rich region. Furthermore, the binding of copper protects GroEL1 from destabilization and increases GroEL1 ATPase activity. Altogether, these findings suggest that GroEL1 could counteract copper toxicity, notably in the macrophage phagosome, and further emphasizes that M. tuberculosis GroEL1 could be an interesting antitubercular target.
结核病病原体结核分枝杆菌难以根除，这是由多种因素导致的，这些因素使细菌能够从应激状态中逃脱。结核分枝杆菌伴侣蛋白GroEL1在进入巨噬细胞后以及在氧化应激下会过量产生，它可能是其中的关键因素之一。我们之前报道过，GroEL1对于结核菌酸海藻糖二霉菌酸酯（一种与毒力相关的脂质）的生物合成以及降低抗生素敏感性是必需的。在本研究中，我们表明，带有独特富含组氨酸的C末端区域的GroEL1，对于牛分枝杆菌卡介苗生物膜生长过程中的铜耐受性是必需的。质谱分析表明，GroEL1对铜离子具有高亲和力，尤其是在其富含组氨酸的C末端区域。此外，铜的结合可保护GroEL1免于不稳定，并增加GroEL1的ATP酶活性。总之，这些发现表明GroEL1可以抵消铜毒性，特别是在巨噬细胞吞噬体中，并且进一步强调结核分枝杆菌GroEL1可能是一个有趣的抗结核靶点。
