Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Cell. 2012 Oct 26;48(2):231-41. doi: 10.1016/j.molcel.2012.08.009. Epub 2012 Sep 13.
Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player in bacterial stress response and persistence. We reveal that (p)ppGpp activates global metabolic changes upon starvation, allowing survival by regulating GTP. Combining metabolomics with biochemical demonstrations, we find that (p)ppGpp directly inhibits the activities of multiple GTP biosynthesis enzymes. This inhibition results in robust and rapid GTP regulation in Bacillus subtilis, which we demonstrate is essential to maintaining GTP levels within a range that supports viability even in the absence of starvation. Correspondingly, without (p)ppGpp, gross GTP dysregulation occurs, revealing a vital housekeeping function of (p)ppGpp; in fact, loss of (p)ppGpp results in death from rising GTP, a severe and previously unknown consequence of GTP dysfunction.
细胞会不断根据环境条件调整其代谢，但生存的主要机制仍未被充分理解。我们发现了一种转录后机制，它将饥饿反应与 GTP 动态平衡整合在一起，以允许生存，这是由核苷酸 (p)ppGpp 介导的，(p)ppGpp 是细菌应激反应和持久性的关键参与者。我们揭示了 (p)ppGpp 在饥饿时会激活全局代谢变化，通过调节 GTP 来允许生存。通过代谢组学和生化验证相结合，我们发现 (p)ppGpp 直接抑制多种 GTP 生物合成酶的活性。这种抑制导致枯草芽孢杆菌中 GTP 得到强有力且快速的调节，我们证明这对于维持 GTP 水平在支持生存的范围内是必不可少的，即使在没有饥饿的情况下也是如此。相应地，如果没有 (p)ppGpp，GTP 就会出现严重失调，这揭示了 (p)ppGpp 的一个重要的管家功能；事实上，失去 (p)ppGpp 会导致 GTP 上升而死亡，这是 GTP 功能障碍的一个严重且以前未知的后果。
