Non-enzymatic protein modifications at the interface of metabolism and immunity

Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins' structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.