(p)ppGpp and c-di-AMP Homeostasis Is Controlled by CbpB in Listeria monocytogenes
Bret N. Peterson, Megan K. M. Young, Shukun Luo, Jeffrey Wang, Aaron T. Whiteley, Joshua J. Woodward, Liang Tong, Jue D. Wang, Daniel A. Portnoy
Abstract
Bacteria must efficiently maintain homeostasis of essential molecules to survive in the environment. We found that the levels of c-di-AMP and (p)ppGpp, two nucleotide second messengers that are highly conserved throughout the microbial world, coexist in a homeostatic loop in the facultative intracellular pathogen Listeria monocytogenes . Here, we found that cyclic di-AMP binding protein B (CbpB) acts as a c-di-AMP sensor that promotes the synthesis of (p)ppGpp by binding to RelA when c-di-AMP levels are low. Addition of c-di-AMP prevented RelA activation by binding and sequestering CbpB. Previous studies showed that (p)ppGpp binds and inhibits c-di-AMP phosphodiesterases, resulting in an increase in c-di-AMP. This pathway is controlled via direct enzymatic regulation and indicates an additional mechanism of ribosome-independent stringent activation.