Crosstalk between (p)ppGpp and other nucleotide second messengers

In response to environmental cues, bacteria produce intracellular nucleotide messengers to regulate a wide variety of cellular processes and physiology. Studies on individual nucleotide messengers, such as (p)ppGpp or cyclic (di)nucleotides, have established their respective regulatory themes. As research on nucleotide signaling networks expands, recent studies have begun to uncover various crosstalk mechanisms between (p)ppGpp and other nucleotide messengers, including signal conversion, allosteric regulation, and target competition. The multiple layers of crosstalk implicate that (p)ppGpp is intricately linked to different nucleotide signaling pathways. From a physiological perspective, (p)ppGpp crosstalk enables fine-tuning and feedback regulation with other nucleotide messengers to achieve optimal adaptation. •Bacteria utilize nucleotide second messengers such as (p)ppGpp as stress regulators.•Crosstalk exists between nucleotide second messenger signaling pathways.•(p)ppGpp crosstalk with other second messenger pathways through different mechanisms.•(p)ppGpp crosstalk enables coordinated regulation to optimize stress adaptation.