C-di-AMP: An Essential Molecule in the Signaling Pathways that Regulate the Viability and Virulence of Gram-Positive Bacteria.

Tazin Fahmi,Kyu Cho,Gary Port

doi:10.3390/genes8080197

Abstract

Signal transduction pathways enable organisms to monitor their external environment and adjust gene regulation to appropriately modify their cellular processes. Second messenger nucleotides including cyclic adenosine monophosphate (c-AMP), cyclic guanosine monophosphate (c-GMP), cyclic di-guanosine monophosphate (c-di-GMP), and cyclic di-adenosine monophosphate (c-di-AMP) play key roles in many signal transduction pathways used by prokaryotes and/or eukaryotes. Among the various second messenger nucleotides molecules, c-di-AMP was discovered recently and has since been shown to be involved in cell growth, survival, and regulation of virulence, primarily within Gram-positive bacteria. The cellular level of c-di-AMP is maintained by a family of c-di-AMP synthesizing enzymes, diadenylate cyclases (DACs), and degradation enzymes, phosphodiesterases (PDEs). Genetic manipulation of DACs and PDEs have demonstrated that alteration of c-di-AMP levels impacts both growth and virulence of microorganisms. Unlike other second messenger molecules, c-di-AMP is essential for growth in several bacterial species as many basic cellular functions are regulated by c-di-AMP including cell wall maintenance, potassium ion homeostasis, DNA damage repair, etc. c-di-AMP follows a typical second messenger signaling pathway, beginning with binding to receptor molecules to subsequent regulation of downstream cellular processes. While c-di-AMP binds to specific proteins that regulate pathways in bacterial cells, c-di-AMP also binds to regulatory RNA molecules that control potassium ion channel expression in Bacillus subtilis. c-di-AMP signaling also occurs in eukaryotes, as bacterially produced c-di-AMP stimulates host immune responses during infection through binding of innate immune surveillance proteins. Due to its existence in diverse microorganisms, its involvement in crucial cellular activities, and its stimulating activity in host immune responses, c-di-AMP signaling pathway has become an attractive antimicrobial drug target and therefore has been the focus of intensive study in several important pathogens.

Highlights

Living organisms receive and process environmental stimuli through signal transduction pathways and respond through differential regulation of various cellular processes
Several additional cyclic nucleotide second messengers have been discovered including cyclic guanosine monophosphate, cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and cyclic guanosine monophosphate-adenosine monophosphate in a wide variety of organisms [2,8,9]. cGMP and c-di-GMP have been well characterized, in Gram-negative bacteria. cGMP is involved in chemotaxis and UV stress-response, while c-di-GMP facilitates the transition from motile phase to adhesive phase and the expression of fimbriae in bacteria [3]
Each of the second messenger nucleotides bind to different sets of proteins or RNA molecules, which thereby regulate distinct cellular processes [17]. c-di-AMP works in the signaling pathway in a manner similar to other second messenger molecules such as c-di-GMP, cyclic adenosine monophosphate (cAMP), and cGMP, but the environmental stimuli and detailed mechanisms are not yet known

Summary

Introduction

Living organisms receive and process environmental stimuli through signal transduction pathways and respond through differential regulation of various cellular processes. Genes 2017, 8, 197 changes such as stress, temperature, nutrition, and pH in both prokaryotes and eukaryotes [1,2,3] As second messengers, these cyclic nucleotides are involved in the transmission of the signals to effector molecules [1,4]. C-di-AMP has been implicated in diverse essential cellular processes including cell wall and membrane homeostasis, regulation of potassium ion channels, DNA damage repair, and sporulation (Table 1). DNA integrity CdaA mutation: impaired potassium ion channel system, weakened cell wall, increased resistance to antibiotics CdaS mutation: delayed sporulation. C-di-AMP works in the signaling pathway in a manner similar to other second messenger molecules such as c-di-GMP, cAMP, and cGMP, but the environmental stimuli and detailed mechanisms are not yet known Each of the second messenger nucleotides bind to different sets of proteins or RNA molecules, which thereby regulate distinct cellular processes [17]. c-di-AMP works in the signaling pathway in a manner similar to other second messenger molecules such as c-di-GMP, cAMP, and cGMP, but the environmental stimuli and detailed mechanisms are not yet known

Synthesis of c-di-AMP

CabPA and CabPB

Conclusions