Chen Yue, Hagopian Berge, Tan Shumin
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
PLoS Pathog. 2025 May 22;21(5):e1013207. doi: 10.1371/journal.ppat.1013207. eCollection 2025 May.
Potassium (K+) is the most abundant intracellular cation, but much remains unknown regarding how K+ homeostasis is integrated with other key bacterial biology aspects. Here, we show that K+ homeostasis disruption (CeoBC K+ uptake system deletion) impedes Mycobacterium tuberculosis (Mtb) response to, and growth in, cholesterol, a critical carbon source during infection, with K+ augmenting activity of the Mtb ATPase MceG that is vital for bacterial cholesterol import. Reciprocally, cholesterol directly binds to CeoB, modulating its function, with a residue critical for this interaction identified. Finally, cholesterol binding-deficient CeoB mutant Mtb are attenuated for growth in lipid-rich foamy macrophages and in vivo colonization. Our findings raise the concept of a role for cholesterol as a key co-factor, beyond its role as a carbon source, and illuminate how changes in intrabacterial K+ levels can act as part of the metabolic adaptation critical for bacterial survival and growth in the host.
钾离子（K+）是细胞内最丰富的阳离子，但关于K+稳态如何与其他关键细菌生物学方面整合，仍有许多未知之处。在此，我们表明K+稳态破坏（CeoBC K+摄取系统缺失）会阻碍结核分枝杆菌（Mtb）对胆固醇（感染期间的关键碳源）的反应及其在胆固醇中的生长，K+可增强对细菌胆固醇摄取至关重要的Mtb ATP酶MceG的活性。相反，胆固醇直接与CeoB结合，调节其功能，并鉴定出了对此相互作用至关重要的一个残基。最后，胆固醇结合缺陷的CeoB突变型Mtb在富含脂质的泡沫巨噬细胞中的生长和体内定殖能力减弱。我们的研究结果提出了胆固醇作为关键辅助因子的作用这一概念，超越了其作为碳源的作用，并阐明了细菌内K+水平的变化如何作为对细菌在宿主中生存和生长至关重要的代谢适应的一部分发挥作用。
