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

As a near-ubiquitous bacterial second messenger, cyclic di-GMP (c-di-GMP) regulates a multitude of important biological processes. The regulatory effects of c-di-GMP on bacterial physiological processes are mediated through its interaction with various effector molecules, including mRNA riboswitches and proteins. Although c-di-GMP effector proteins have been widely reported, yet unknown c-di-GMP effectors in bacteria wait to be discovered, and the physiological roles of this second messenger still remain to be explored. In a c-di-GMP/transcription factor binding screen, we identified NadR, a repressor of nicotinamide adenine dinucleotide (NAD) synthesis and salvage, as a c-di-GMP-responsive transcription factor in IMPORTANCE: 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