Fig 1: Metrnl promotes the interaction of STING with TRAF2 in mitochondria to induce STING ubiquitination and degradation in cardiomyocytes. (A) Effects of Metrnl on TRAF2 in mitochondria. (B) Effects of Metrnl shRNA on TRAF2 in mitochondria. (C) Confocal images showing the colocalization of STING with TRAF2 in cardiomyocytes. (D) Co-IP showing the interaction of STING with TRAF2. (E) Effects of Metrnl on the STING/TRAF2 complex. (F) Effects of Metrnl shRNA on the STING/TRAF2 complex. (G) A proteasome inhibitor MG132 prevented the suppressive effects of Metrnl on STING protein expression. (H) Half-life of STING in different groups. (I) Effects of Metrnl (left) or Metrnl shRNA (right) on the ubiquitination of STING. (J) OE of LKB1 prevented the actions of Metrnl shRNA on the ubiquitination of STING. (K) STING siRNA and TRAF2 siRNA weakened the effects of Metrnl on the p62 and LC3 proteins. (L) STING siRNA and TRAF2 siRNA weakened the effects of Metrnl on the formation of autophagosome as assessed by LC3 dots. n = 4. *P < 0.05 versus 0 h, NG, Con, or Con shRNA, †P < 0.05 versus HG + Con shRNA, Metrnl or HG, ‡ P < 0.05 versus HG + Metrnl + Con siRNA.
Fig 2: ULK1 phosphorylation is required for Metrnl to inactivate the cGAS/STING signaling in cardiomyocytes. (A) Effects of Metrnl on cGAS, phosphorylated STING, and total STING. (B) Effects of Metrnl shRNA on cGAS, phosphorylated STING, and total STING. (C) Effects of Metrnl (upper) or Metrnl shRNA (lower) on STING in mitochondria. (D) Effects of Con siRNA and ULK1 siRNA on ULK1 protein. (E) Silencing of ULK1 abolished the inhibitory effects of Metrnl on cGAS, phosphorylated STING, total STING and STING in mitochondria. n = 4. *P < 0.05 versus NG or Con shRNA, †P < 0.05 versus HG + Con shRNA or HG, ‡ P < 0.05 versus HG + Metrnl + Con siRNA.
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