The Estrogen Receptor-Related Orphan Receptors Regulate Autophagy Through TFEB

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) play fundamental role in regulation of cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce autophagy in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12 myoblasts. ERR-dependent increases in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for treatment of many diseases where stimulation of autophagy may be therapeutic including heart failure.### Competing Interest StatementThe authors have declared no competing interest.* BAF : bafilomycin A1 ChIP-seq : chromatin immunoprecipitation with high-throughput sequencing CLEAR : Coordinated Lysosomal Expression and Regulation DMEM : Dulbecco’s modified Eagle’s medium DMSO : dimethyl sulfoxide ERR : estrogen related receptor ERRE : estrogen related receptor response element FAO : fatty acid oxidation GFP : green fluorescent protein hiPSC-CM : human induced pluripotent stem cell-derived cardiomyocytes MAPK1 : Mitogen-activated protein kinase 1 MOI : Multiplicity of infection mTORC1 : mammalian target of rapamycin complex 1 NCOR1 : Nuclear Receptor Corepressor 1 OXPHOS : oxidative phosphorylation PGC1a : peroxisome proliferator-activated receptor gamma coactivator 1-alpha PKC : protein kinase c RFP : red fluorescent protein TAC : transverse aortic constriction TCA : tricarboxylic acid cycle TFEB : transcription factor EB