Exploring Protein Carboxylation: A Molecular Mechanism for CO2 Sensing in Human Health and Disease

CO2 is a common biological gas that triggers adaptive responses in various organisms. In humans, it’s abundantly produced as a byproduct of oxidative respiration and plays crucial roles in health and disease. For example, elevated CO2 levels can lead to airway constriction and respiratory distress. Additionally, pathogens like Enteropathogenic Escherichia coli use CO2 within the human host as a crucial cue to trigger virulence. Targeting these CO2-dependent responses offers significant potential for therapeutic development. However, understanding the fundamental biochemical mechanisms of CO2 sensing is crucial and remains largely unexplored. A promising mechanism involves CO2 forming a reversible covalent bond with specific protein sites, called Prot-CO2, which acts as a regulatory switch. However, this mechanism is scarcely characterized due to a lack of identification methods. Here, we present a suite of innovative high-throughput techniques for discovering Prot-CO2 sites across the proteome and illuminate their detailed biochemical mechanisms of sensing. By studying CO2 sensing in pathogens and airway constriction, we aim to uncover knowledge that can be used to develop new therapeutic approaches targeting cellular CO2 sensing.