biostudies-literatureSun D| Natural Science Foundation of Xuzhou Municipality (Xuzhou Natural Science Foundation)JST | Jiangsu Natural Science Foundation | Basic Research Program of Jiangsu ProvinceMOST | National Natural Science Foundation of China (NSFC)徐州市科学技术局 | Natural Science Foundation of Xuzhou MunicipalityMOST | National Natural Science Foundation of ChinaScientific Experiment Project of China Space Statione2516964122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12415220biostudies-literatureUnknown122(35)Bacteria have several nucleotide second messengers, most of which act as global regulators to control a wide range of bacterial physiological processes. Studies usually focus on a single second messenger, and the mechanisms and physiological significance of the cross-regulation between different nucleotide second messengers are often unclear. Here, we show that <i>Shewanella putrefaciens</i> can form biofilms in both nutrient-rich and nutrient-poor media. While both are controlled by c-di-GMP, the regulatory models differ. Under low nutrient conditions, cross-regulation of cAMP-CRP and c-di-GMP occurs at the transcriptional and posttranslational levels, thereby controlling biofilm development. During the early stages of biofilm development, cAMP-CRP directly promotes the transcription of aProceedings of the National Academy of Sciences of the United States of AmericaLocal c-di-GMP signaling, triggered by cross-regulation of cAMP-CRP and c-di-GMP, controls biofilm formation under nutrient limitation.PMC124152203197003632401044BK202109203190040132370583KC23301BK20241961KJZ-YY-NSM051832370023BK2023135032270119Liu XYang JLiu JShi RZhu JZhang YSun DChen YRu YLiu CZhou XLiu WfalseLocal c-di-GMP signaling, triggered by cross-regulation of cAMP-CRP and c-di-GMP, controls biofilm formation under nutrient limitation.Bacteria have several nucleotide second messengers, most of which act as global regulators to control a wide range of bacterial physiological processes. Studies usually focus on a single second messenger, and the mechanisms and physiological significance of the cross-regulation between different nucleotide second messengers are often unclear. Here, we show that <i>Shewanella putrefaciens</i> can form biofilms in both nutrient-rich and nutrient-poor media. While both are controlled by c-di-GMP, the regulatory models differ. Under low nutrient conditions, cross-regulation of cAMP-CRP and c-di-GMP occurs at the transcriptional and posttranslational levels, thereby controlling biofilm development. During the early stages of biofilm development, cAMP-CRP directly promotes the transcription of a2025-01-01T00:00:00Z2025 Sep2026-06-02T02:44:42.97Z2026-04-13T03:12:49.292ZS-EPMC124152204085412410.1073/pnas.2516964122