title: Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.
abstract: 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.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Kriel
authors.forename: Alycia N
authors.initials: AN
authors.lastname: Bittner
authors.forename: Sok Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Kuanqing
authors.initials: K
authors.lastname: Liu
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Tehranchi
authors.forename: Winnie Y
authors.initials: WY
authors.lastname: Zou
authors.forename: Samantha
authors.initials: S
authors.lastname: Rendon
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Tu
authors.forename: Jue D
authors.initials: JD
authors.lastname: Wang
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D001412:Bacillus subtilis / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D004926:Escherichia coli / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D011755:Pyrophosphatases / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000596:Amino Acids; D006160:Guanosine Triphosphate; D011755:Pyrophosphatases