Research ArticleMicrobiology

The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus

Sci. Signal.  16 Aug 2016:
Vol. 9, Issue 441, pp. ra81
DOI: 10.1126/scisignal.aaf7279

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c-di-AMP inhibits the Staphylococcus aureus response to osmotic stress

Like other bacteria, the opportunistic pathogen Staphylococcus aureus responds to increases in osmolarity by taking up potassium ions and either taking up or synthesizing compatible solutes, small organic molecules that act as osmolytes. These measures prevent the toxic accumulation of sodium ions inside the cell and prevent water loss. Schuster et al. identified OpuCA, a component of the osmolyte uptake system OpuC, as a receptor for cyclic diadenosine monophosphate (c-di-AMP) in S. aureus. Recombinant OpuCA bound to c-di-AMP in vitro, and a crystal structure revealed a putative binding pocket for c-di-AMP. OpuC mediated the uptake of carnitine, but not other compatible solutes, under osmotic stress, and c-di-AMP reduced OpuC-mediated carnitine uptake. Because c-di-AMP also inhibits potassium uptake, these findings implicate c-di-AMP as an inhibitor of both potassium and compatible solute uptake for osmoprotection.

Abstract

Staphylococcus aureus is an important opportunistic human pathogen that is highly resistant to osmotic stresses. To survive an increase in osmolarity, bacteria immediately take up potassium ions and small organic compounds known as compatible solutes. The second messenger cyclic diadenosine monophosphate (c-di-AMP) reduces the ability of bacteria to withstand osmotic stress by binding to and inhibiting several proteins that promote potassium uptake. We identified OpuCA, the adenosine triphosphatase (ATPase) component of an uptake system for the compatible solute carnitine, as a c-di-AMP target protein in S. aureus and found that the LAC*ΔgdpP strain of S. aureus, which overproduces c-di-AMP, showed reduced carnitine uptake. The paired cystathionine-β-synthase (CBS) domains of OpuCA bound to c-di-AMP, and a crystal structure revealed a putative binding pocket for c-di-AMP in the cleft between the two CBS domains. Thus, c-di-AMP inhibits osmoprotection through multiple mechanisms.

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