Cyclic di-AMP, a multifaceted regulator of central metabolism and osmolyte homeostasis in Listeria monocytogenes

Abstract

Cyclic di-AMP is an emerging second messenger that is synthesized by many archaea and bacteria, including the Gram-positive pathogenic bacterium Listeria monocytogenes. Listeria monocytogenes played a crucial role in elucidating the essential function of c-di-AMP, thereby becoming a model system for studying c-di-AMP metabolism and the influence of the nucleotide on cell physiology. c-di-AMP is synthesized by a diadenylate cyclase and degraded by two phosphodiesterases. To date, eight c-di-AMP receptor proteins have been identified in L. monocytogenes, including one that indirectly controls the uptake of osmotically active peptides and thus the cellular turgor. The functions of two c-di-AMP-receptor proteins still need to be elucidated. Here, we provide an overview of c-di-AMP signalling in L. monocytogenes and highlight the main differences compared to the other established model systems in which c-di-AMP metabolism is investigated. Moreover, we discuss the most important questions that need to be answered to fully understand the role of c-di-AMP in osmoregulation and in the control of central metabolism.

Keywords: CodY; Osmolyte; essential gene; osmoregulation; second messenger; turgor.

Figure 1.

Schematic illustration of c-di-AMP signalling in L. monocytogenes (modified from Wang et al. 2022). CdaR and GlmM modulate the activity of CdaA. c-di-AMP is secreted by multidrug efflux pumps (MDRs) and degraded by the phosphodiesterases GdpP and PgpH to 5′-pApA. The nanoRNase NrnA converts 5′pApA to AMP. The uptake of potassium and carnitine is inhibited by c-di-AMP that also interacts with the sensor kinase of the putative kdpABC potassium transporter genes. c-di-AMP indirectly controls the CodY-dependent expression of the opp oligopeptide transporter genes via CbpB-dependent regulation of Rel activity. The Opp system is involved in the uptake of bialaphos and fosfomycin of which the latter is also imported by the hexose phosphate transporter Hpt. Fosfomycin inhibits the UDP-N-acetylglucosamine 1-carboxyvinyltransferase MurA. The activity of the PycA pyruvate carboxylase is allosterically regulated by c-di-AMP. The functions of the c-di-AMP receptor proteins CbpA and PstA are unknown.