Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling

Abstract

Sepsis: chemical modulation of selective autophagy alleviates systemic inflammationSepsis is a life-threatening condition that occurs when the body's response to infection damages its own organs. Autophagy protects the body by degrading harmful materials in the cell using the lysosome. It has been an outstanding question whether autophagy can fight systemic inflammation in sepsis. Researchers in South Korea led by Eun-Kyeong Jo at Chungnam National University and Yong Tae Kwon at Seoul National University developed small molecule chemicals that target the autophagic receptor p62/SQSTSM-1/Sequestosome-1 to induce therapeutic efficacy during septic responses. In a mouse model of septic shock, these orally administrative compounds halted the production of proinflammatory molecules and reduced oxidative stress in mitochondria by facilitating the autophagic turnover of damaged mitochondria. Chemical modulation of p62 is now emerging as a therapeutic strategy to treat sepsis responsible for 11 million deaths a year. The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.