The ever-expanding world of bacterial cyclic oligonucleotide second messengers

Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the identification of 3'-5', 3'-5' cyclic di-GMP (c-di-GMP) in 1987, a second messenger that is now known to be the linchpin signaling pathway modulating bacterial motility and biofilm formation. In the past 15 years, three more cdNs were uncovered: 3'-5', 3'-5' cyclic di-AMP (c-di-AMP) and 3'-5', 3'-5' cyclic GMP-AMP (3',3' cGAMP) in bacteria and 2'-5', 3'-5' cyclic GMP-AMP (2',3' cGAMP) in eukaryotes. We now appreciate that bacteria can synthesize many varieties of cdNs from every ribonucleotide, and even cyclic trinucleotide (ctN) second messengers have been discovered. Here we highlight our current understanding of c-di-GMP and c-di-AMP in bacterial physiology and focus on recent advances in 3',3' cGAMP signaling effectors, its role in bacterial phage response, and the diversity of its synthase family.