Cyclic nucleotide signaling in Mycobacterium tuberculosis: an expanding repertoire

Abstract

Mycobacterium tuberculosis (Mtb) is one of the most successful microbial pathogens, and currently infects over a quarter of the world's population. Mtb's success depends on the ability of the bacterium to sense and respond to dynamic and hostile environments within the host, including the ability to regulate bacterial metabolism and interactions with the host immune system. One of the ways Mtb senses and responds to conditions it faces during infection is through the concerted action of multiple cyclic nucleotide signaling pathways. This review will describe how Mtb uses cyclic AMP, cyclic di-AMP and cyclic di-GMP to regulate important physiological processes, and how these signaling pathways can be exploited for the development of novel thereapeutics and vaccines.

Figure 1.

Cyclic nucleotide signaling pathway. Organisms from all domains of life use cyclic nucleotide (cNT) signaling pathways to coordinate cellular responses with extra and intracellular signals. (I) Nucleotide cyclases are either activated by an associated receptor or by directly sensing an environmental signal. (II) Once activated the cyclase converts a linear nucleotide substrate to the cNT second messenger, which can be degraded by phosphodiesterase (PDE) enzymes. (III) The cNT then interacts with downstream effectors, either proteins or regulatory RNAs, altering their function. (IV) This ultimately converts signals into cellular responses.

Figure 2.

cAMP signaling pathway in Mtb. cAMP signaling in Mtb is complex, involving up to 16 ACs, 10 of which have been biochemically shown to produce cAMP shown here. Rv1264, Rv1647, Rv2212, Rv1319c and Rv1625c are activated by known signals, including pH, fatty acids, protein-protein interactions and small molecules. The other five enzymes with confirmed AC activity have not been associated with specific signals. Mtb produces high levels of cAMP upon macrophage infection, growth on propionate or exposure to heat stress; however, the specific signals and ACs responsible are not known. Mtb can control the level of cAMP available in the cytoplasm by regulation of synthesis, hydrolysis via the Rv0805 PDE, secretion outside of the cell and by Rv1636 binding. There are 10 proteins with cNT-binding domains (CNBs), only Rv3676 (CRP_MT), Rv1675c (Cmr) and Rv0998 (MtPat) have been characterized. CRP_MT and Cmr are DNA-binding transcription factors (TF) that regulate mycobacterial gene expression, while MtPat is a lysine acetyl transferase that is activated by cAMP to inactivate downstream protein substrates.

Figure 3.

Model for cNT signaling in Mtb. Mtb produces the cNT second messengers cAMP, c-di-AMP and c-di-GMP to control key bacterial processes. Despite differences between the specific molecular players, all three signaling pathways involve nucleotide cyclases (pale blue), PDEs (red) and protein effectors (blue). Additionally, all three cNTs play important roles in interspecies signaling between Mtb and mammalian innate immune cells. More work is required to determine the specific signaling outcomes for each cNT pathway, and to identify the exact roles played by cNTs during different stages of Mtb infection.