The muscle‐specific ubiquitin ligase MuRF1 regulates autophagy via FOXO1/3 ubiquitination to inhibit NF‐κB signaling and protect against cardiac inflammation in vivo

Abstract

The muscle‐specific ubiquitin ligase MuRF1 (muscle ring finger‐1) has recently been shown to regulate signal transduction by modulating transcription factor activity through ubiquitin‐mediated post‐translational modification. Therefore, we investigated the ability of MuRF1 to regulate autophagy. MuRF1−/− hearts exhibited decreased autophagic flux (decrease in LC3II and VPS34 protein levels), while MuRF1Tg+ hearts exhibited increased autophagic flux (increase in last phase autophagosomes and VPS34 protein levels). Interestingly, the FOXO1/3a transcription factors, known supporters of autophagy, correlated with MuRF1 expression. MuRF1−/− hearts expressed significantly less of the FOXO‐regulated P62, while MuRF1Tg+ expressed significantly more P62 by immunoblot analysis. Since P62 supports NF‐κB signaling by IKKβ phosphorylation, MuRF1−/− and MuRF1Tg+ mice were challenged with LPS to determine resistance to endotoxin‐induced cardiac dysfunction to identify the role of MuRF1‐P62 in inhibiting cardiac NF‐κB signaling. MuRF1−/− mice were significantly protected against LPS‐induced systolic dysfunction, while MuRF1 Tg+ mice were more susceptible to LPS‐induced heart failure. NF‐κB activity was significantly inhibited in MuRF1−/− mice at the level of the IKK complex, consistent with decreased FOXO‐regulated P62 to reduce downstream NF‐κB signaling. These studies identify the first ubiquitin ligase to regulate autophagy in the heart and describe novel therapeutic targets that could be used to block myocyte‐specific inflammationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.