Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.

TitleDirect regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.
Publication TypeJournal Article
Year of Publication2012
AuthorsKriel, A, Bittner, AN, Kim, SHo, Liu, K, Tehranchi, AK, Zou, WY, Rendon, S, Chen, R, Tu, BP, Wang, JD
JournalMol Cell
Volume48
Issue2
Pagination231-41
Date Published2012 Oct 26
ISSN1097-4164
KeywordsAmino Acids, Bacillus subtilis, Cell Survival, Escherichia coli, Guanosine Triphosphate, Humans, Pyrophosphatases, Stress, Physiological
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.

DOI10.1016/j.molcel.2012.08.009
Alternate JournalMol. Cell
PubMed ID22981860
PubMed Central IDPMC3483369
Grant ListR01 GM084003 / GM / NIGMS NIH HHS / United States
R01 GM094314 / GM / NIGMS NIH HHS / United States
R01GM094314 / GM / NIGMS NIH HHS / United States
T90 DA022885 / DA / NIDA NIH HHS / United States
R01GM084003 / GM / NIGMS NIH HHS / United States

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