Cyclic AMP signalling in mycobacteria: redirecting the conversation with a common currency

Abstract

cAMP is an ancient second messenger, and is used by many organisms to regulate a wide range of cellular functions. Mycobacterium tuberculosis complex bacteria are exceptional in that they have genes for at least 15 biochemically distinct adenylyl cyclases, the enzymes that generate cAMP. cAMP-associated gene regulation within tubercle bacilli is required for their virulence, and secretion of cAMP produced by M. tuberculosis bacteria into host macrophages disrupts the host's immune response to infection. In this review, we discuss recent advances in our understanding of the means by which cAMP levels are controlled within mycobacteria, the importance of cAMP to M. tuberculosis during host infection, and the role of cAMP in mycobacterial gene regulation. Understanding the myriad aspects of cAMP signalling in tubercle bacilli will establish new paradigms for cAMP signalling, and may contribute to new approaches for prevention and/or treatment of tuberculosis disease.

Figure 1

Possible M. tuberculosis cAMP signaling pathways are illustrated. Adenyl cyclases (double circles, designated as AC1–3) can be activated by intra- or extracellular signals (arrows) to produce cAMP (represented as triangles). Some cyclases may directly respond to the activating signal, as indicated for AC1 and AC2, while intermediary receptors may transmit the signal to others, as shown for AC3, where ‘R’ is a receptor protein. cAMP is then bound to effector proteins (pentagons), which have functions in gene regulation, protein acetylation or other yet to be described activities, possibly including small molecule transport (indicated as yellow dots). cAMP can also be degraded by a phosphodiesterase (PDE), or exported, as shown. Yellow stars represent proteins, some of which are expressed from cAMP-responsive transcription factors, and the orange dot represents acetylation. Different colors are used to indicate that diversity, and likely specificity, exists at the signal, cyclase and effector levels.