GSE185754
Cardiomyocyte TLR4 regulates autophagy through TRAF6-mediated TFEB ubiquitination in sepsis-associated cardiac dysfunction
Sepsis-associated cardiac dysfunction (SACD) is the predominant cause of death in sepsis patients with undefined mechanism of inflammation-autophagy interaction to date. Herein, time-course analysis of cardiac autophagy was conducted in a mouse model of SCAD. An in vitro model established by Lipopolysaccharide-induced macrophage conditioned media stimulation on cardiomyocytes was further investigated for molecular insights. We show cardiomyocyte Toll-like receptor 4 (cTLR4) serves as a central receptor mediating the crosstalk between cardiomyocyte and macrophage, and activation of cTLR4 intensifies the impairment of autophagic flux in cardiomyocytes. Mechanistically, the activation of cTLR4 inactivates TFEB, which largely depends on the E3 ligase activity of TRAF6. Moreover, computational simulation combined with experimental validation revealed the unique local electrostatic interactions between TRAF6 and TFEB. Collectively, our results highlight a previously undescribed role of cTLR4-TRAF6-TFEB signaling in modulating cardiac injury and identify the TRAF6-binding motif in TFEB as an attractive target for SACD therapy. Overall design: Cardiac mRNA profiles of saline-injected control mice and LPS-stressed 24 h mice