c-di-GMP regulates bacterial NAD biosynthesis via targeting the transcriptional repressor NadR

Cyclic di-GMP (c-di-GMP) functions as a highly versatile signaling molecule in bacteria, orchestrating diverse physiological processes critical for survival and adaptation. While nicotinamide adenine dinucleotide (NAD) plays pivotal roles in numerous cellular processes and functions, bacteria have been shown to modulate its biosynthetic and recycling pathways through a variety of regulatory mechanisms. However, a connection between c-di-GMP signaling and NAD metabolism in bacteria has never been revealed before. Here, we identify NadR, a transcriptional repressor of NAD synthesis and salvage, as a c-di-GMP effector, and show that c-di-GMP upregulates NAD biosynthesis by activating NadR-repressed genes, thus enhancing the defense of <i>Salmonella</i> against DNA damage. Our study reveals a previously unrecognized regulatory mechanism in bacterial NAD metabolism and expands the understanding of the physiological roles of c-di-GMP in bacteria.