Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway.
Jiao LiuYichun WangLing ZengChunhua YuRui KangDaniel J KlionskyJianxin JiangDaolin TangPublished in: Autophagy (2024)
Sepsis, a life-threatening condition resulting from a dysregulated response to pathogen infection, poses a significant challenge in clinical management. Here, we report a novel role for the autophagy receptor NCOA4 in the pathogenesis of sepsis. Activated macrophages and monocytes secrete NCOA4, which acts as a mediator of septic death in mice. Mechanistically, lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria, induces NCOA4 secretion through autophagy-dependent lysosomal exocytosis mediated by ATG5 and MCOLN1. Moreover, bacterial infection with E. coli or S. enterica leads to passive release of NCOA4 during GSDMD-mediated pyroptosis. Upon release, extracellular NCOA4 triggers the activation of the proinflammatory transcription factor NFKB/NF-κB by promoting the degradation of NFKBIA/IκB molecules. This process is dependent on the pattern recognition receptor AGER, rather than TLR4. In vivo studies employing endotoxemia and polymicrobial sepsis mouse models reveal that a monoclonal neutralizing antibody targeting NCOA4 or AGER delays animal death, protects against organ damage, and attenuates systemic inflammation. Furthermore, elevated plasma NCOA4 levels in septic patients, particularly in non-survivors, correlate positively with the sequential organ failure assessment score and concentrations of lactate and proinflammatory mediators, such as TNF, IL1B, IL6, and HMGB1. These findings demonstrate a previously unrecognized role of extracellular NCOA4 in inflammation, suggesting it as a potential therapeutic target for severe infectious diseases.
Keyphrases
- acute kidney injury
- oxidative stress
- signaling pathway
- transcription factor
- intensive care unit
- end stage renal disease
- infectious diseases
- cell death
- lps induced
- endoplasmic reticulum stress
- chronic kidney disease
- inflammatory response
- septic shock
- escherichia coli
- ejection fraction
- newly diagnosed
- immune response
- type diabetes
- mouse model
- peritoneal dialysis
- adipose tissue
- drug delivery
- cancer therapy
- gene expression
- genome wide
- dendritic cells
- dna methylation
- zika virus
- prognostic factors
- patient reported outcomes
- skeletal muscle
- candida albicans
- single cell
- listeria monocytogenes
- aedes aegypti
- dengue virus