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KMID : 0620920230550020333
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Experimental & Molecular Medicine
2023 Volume.55 No. 2 p.333 ~ p.346
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Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling
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Prashanta Silwal
Kim Young-Jae
Lee Yoon-Jee
Kim In-Soo
Jeon Sang-Min
Taylor Roh
Kim Jin-Kyung
Lee Min-Joung
Heo Jun-Young
Kim Byung-Kwan
Lee Sang-Hee
Cho Dong-Hyung
Kim Jin-Man
Kwon Yong-Tae
Ryu Seung-Jae
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Abstract
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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.
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KEYWORD
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Mitophagy, Sepsis
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