title: The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination.
abstract: The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARα, but not PPARβ/δ or PPARγ in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARα activity and acyl-carnitine intermediates, while MuRF1-/- hearts exhibited increased PPARα activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARα, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARα, along with three specific lysines (292, 310, 388) required for MuRF1's targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARα, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Rodríguez
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jie-Ying
authors.initials: JY
authors.lastname: Liao
authors.affiliation: General Hospital of Ningxia Medical University, Yinchuan, Ningxia, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and the Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Doreen
authors.initials: D
authors.lastname: Drujan
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: C Brandon
authors.initials: CB
authors.lastname: Frederick
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Yoder
authors.affiliation: Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Lalush
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA. Electronic address: monte_willis@med.unc.edu.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D009124:Muscle Proteins; D047493:PPAR alpha; D000070584:Tripartite Motif Proteins; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Cardiac metabolism; Cardiomyocyte; Fatty acid metabolism; Monoubiquitination; Muscle ring finger-1; Peroxisome proliferator-activated receptor α