TY - JOUR
T1 - Direct regulation of GTP homeostasis by (p)ppGpp
T2 - A critical component of viability and stress resistance
AU - Kriel, Allison
AU - Bittner, Alycia N.
AU - Kim, Sok Ho
AU - Liu, Kuanqing
AU - Tehranchi, Ashley K.
AU - Zou, Winnie Y.
AU - Rendon, Samantha
AU - Chen, Rui
AU - Tu, Benjamin P.
AU - Wang, Jue D.
N1 - Funding Information:
We thank S. Stibitz, J. Berger, R. Britton, and M. Cashel for reagents; E. White for help on the manuscript; and G. Allen, B. Bochner, S. Brinsmade, M. Cashel, R. Gourse, C. Herman, S. Rosenberg, W. Ross, L. Sonenshein, J. Wilson, and the Wang Lab for discussions and comments. J.D.W. is supported by NIGMS R01GM084003 and Welch Grant Q-1698. B.P.T. is supported by NIGMS R01GM094314 and Welch Grant I-1697. A.N.B. was supported by a fellowship from GCC (T90 DA022885-05).
PY - 2012/10/26
Y1 - 2012/10/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2012.08.009
DO - 10.1016/j.molcel.2012.08.009
M3 - Article
C2 - 22981860
AN - SCOPUS:84868147753
SN - 1097-2765
VL - 48
SP - 231
EP - 241
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -