A universal stress protein is essential for the survival ofMycobacterium tuberculosis

Mycobacterium tuberculosisemploys several signaling pathways to regulate its cellular physiology and survival within the host. Mycobacterial genomes encode multiple adenylyl cyclases and cAMP effector proteins, underscoring the diverse ways in which these bacteria utilize cAMP. We have earlier identified universal stress proteins (USP), Rv1636 and MSMEG_3811 inM. tuberculosisandM. smegmatisrespectively, as abundantly expressed, novel cAMP-binding proteins. In this study, we show that these USPs may function to regulate cAMP signaling by direct sequestration of the second messenger. In slow-growing mycobacteria, concentrations of Rv1636 were equivalent to the amounts of cAMP present in the cell, and overexpression of Rv1636 inM. smegmatisincreased levels of ‘bound’ cAMP. Rv1636 is secreted via the SecA2 secretion system inM. tuberculosisbut is not directly responsible for the efflux of cAMP from the cell. Whilemsmeg_3811could be readily deleted from the genome ofM. smegmatis, we find that therv1636gene is essential for growth ofM. tuberculosis, and this functionality depends on the cAMP-binding ability of Rv1636. This is the first evidence of a ‘sink’ for any second messenger in bacterial signaling that would allow mycobacterial cells to regulate the available intracellular ‘free’ pool of cAMP.