Endogenous cAMP elevation regulates proteostasis networks to integrate stress signaling, metabolic reprogramming, and...

The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) serves as a critical transducer of environmental signals in plants, yet its systems-level integration of stress-responsive networks remains poorly characterized. To elucidate how cAMP signaling orchestrates long-term global cellular reprogramming, transcriptomic profiling was combined with integrative network analysis in Arabidopsis thaliana having elevated endogenous cAMP. A cohort of 171 cAMP-responsive genes (CRGs) was first defined as anchor nodes of predicted interactions derived from transcriptomic data and constructed a high-confidence protein-protein interaction (PPI) network using the STRING database. Topological analysis revealed HSP90.1 and HSP70.5 as ultra-hubs within a densely interconnected chaperone network, alongside major hubs such as RD29A linking dehydration-responsive transcription and abscisic acid (ABA) biosynthesis. Community detection partitioned the interactome into specialized modules governing proteostasis, cold/drought adaptation, and sulfur/nitrogen metabolism. Prediction-based pathway inference delineated a hierarchical signaling cascade, progressing from kinase-mediated defense activation through proteostasis reinforcement to metabolic and transcriptional reprogramming. Strikingly, cAMP elevation triggered a functional pivot: suppression of broad-spectrum abiotic stress responses and energy-intensive chaperone networks, coupled with selective activation of immune signaling and sulfur-based defense metabolism. KEGG pathway analysis confirmed this reallocation, showing upregulation of linoleic acid metabolism, glutathione homeostasis, and sulfur assimilation, concurrent with downregulation of growth-promoting hormone pathways and central carbon metabolism. This study establishes cAMP not as a linear activator but as a systems-level metabolic switch that reprioritizes cellular resources from constitutive stress preparedness toward active defense and metabolic resilience. These findings provide a comprehensive framework for understanding how second messengers compute stress signals into optimized survival strategies, with implications for engineering stress-adaptive crops.

The online version contains supplementary material available at 10.1007/s12298-026-01757-9.