Cell cycle control and environmental response by second messengers in Caulobacter crescentus

Area of Science:

• Bacterial Physiology
• Systems Biology
• Molecular Biology

Background:

• Second messengers cyclic di-GMP (c-di-GMP) and ppGpp regulate critical bacterial processes including biofilm formation, virulence, and proliferation.
• These nucleotides, synthesized from GTP, exhibit antagonistic roles in cell cycle control, with c-di-GMP governing cell development and ppGpp mediating stress responses.
• The nitrogen phosphotransferase system (PTS ^Ntr) detects glutamine levels, linking nutrient availability to bacterial second messenger pathways via RelA-SpoT homolog enzymes.

Purpose of the Study:

• To develop a mathematical model elucidating the dynamics of c-di-GMP and ppGpp in *C. crescentus*.
• To investigate how the bacterial PTS ^Ntr system influences guanine nucleotide-based second messenger networks in response to nutrient availability.
• To understand the interplay between nutrient signaling and bacterial cell cycle regulation.

Main Methods:

• Formulation of a mathematical model comprising seven ordinary differential equations (ODEs).
• The model describes the dynamic interactions between nucleotides (c-di-GMP, ppGpp, GMP, GTP) and PTS ^Ntr enzymes.
• Simulations of the model to analyze responses to environmental changes communicated through the PTS ^Ntr system.

Main Results:

• Model simulations align with existing experimental observations regarding bacterial responses to nutrient fluctuations.
• The study predicts that SpoT effectively lowers c-di-GMP levels during nitrogen starvation, mirroring its role in increasing ppGpp levels.
• SpoT activity significantly influences both c-di-GMP and ppGpp levels, thereby impacting bacterial cell cycle progression.

Conclusions:

• A novel mathematical model integrates knowledge of bacterial second messengers and nutrient signaling pathways.
• The PTS ^Ntr system's influence on c-di-GMP, ppGpp, GMP, and GTP concentrations is demonstrated through the model.
• This work represents a foundational effort in modeling nutrient signaling in *C. crescentus*, highlighting the interconnectedness of metabolic sensing and cellular regulation.