Department of Chemistry, Indiana University, Bloomington, IN 47405, USA; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cell Chem Biol. 2019 May 16;26(5):745-755.e7. doi: 10.1016/j.chembiol.2019.02.011. Epub 2019 Mar 21.
Calprotectin (CP) inhibits bacterial viability through extracellular chelation of transition metals. However, how CP influences general metabolism remains largely unexplored. We show here that CP restricts bioavailable Zn and Fe to the pathogen Acinetobacter baumannii, inducing an extensive multi-metal perturbation of cellular physiology. Proteomics reveals severe metal starvation, and a strain lacking the candidate Zn metallochaperone ZigA possesses altered cellular abundance of multiple essential Zn-dependent enzymes and enzymes in de novo flavin biosynthesis. The ΔzigA strain exhibits decreased cellular flavin levels during metal starvation. Flavin mononucleotide provides regulation of this biosynthesis pathway, via a 3,4-dihydroxy-2-butanone 4-phosphate synthase (RibB) fusion protein, RibBX, and authentic RibB. We propose that RibBX ensures flavin sufficiency under CP-induced Fe limitation, allowing flavodoxins to substitute for Fe-ferredoxins as cell reductants. These studies elucidate adaptation to nutritional immunity and define an intersection between metallostasis and cellular metabolism in A. baumannii.
钙卫蛋白（CP）通过细胞外螯合过渡金属来抑制细菌活力。然而，CP 如何影响一般代谢在很大程度上仍未得到探索。我们在这里表明，CP 将生物可利用的锌和铁限制在病原体鲍曼不动杆菌上，从而导致细胞生理的广泛多金属扰动。蛋白质组学揭示了严重的金属饥饿，并且缺乏候选锌金属伴侣蛋白 ZigA 的菌株表现出多种必需的锌依赖性酶和从头黄素生物合成中酶的细胞丰度发生改变。在金属饥饿期间，ΔzigA 菌株的细胞黄素水平降低。黄素单核苷酸通过 3,4-二羟基-2-丁酮 4-磷酸合酶（RibB）融合蛋白 RibBX 和真正的 RibB 对该生物合成途径进行调控。我们提出，RibBX 确保了在 CP 诱导的铁限制下黄素的充足，使黄素氧还蛋白能够替代铁铁氧还蛋白作为细胞还原剂。这些研究阐明了对营养免疫的适应，并确定了鲍曼不动杆菌中金属稳态和细胞代谢之间的交点。
