The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination

Jessica E. Rodríguez, Jie Ying Liao, Jun He, Jonathan C. Schisler, Christopher B. Newgard, Doreen Drujan, David J. Glass, C. Brandon Frederick, Bryan C. Yoder, David S. Lalush, Cam Patterson, Monte Willis

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)36-48
Number of pages13
JournalMolecular and Cellular Endocrinology
Volume413
DOIs
StatePublished - Sep 5 2015
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Cell Nucleus Active Transport
Ligases
Ubiquitin
Carnitine
Fatty Acids
Oxidation
Ubiquitination
Proteasome Endopeptidase Complex
Post Translational Protein Processing
Cardiac Myocytes
Metabolism
Fingers
Lysine
Muscle
Heart Failure
Muscles

Keywords

  • Cardiac metabolism
  • Cardiomyocyte
  • Fatty acid metabolism
  • Monoubiquitination
  • Muscle ring finger-1
  • Peroxisome proliferator-activated receptor α

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination. / Rodríguez, Jessica E.; Liao, Jie Ying; He, Jun; Schisler, Jonathan C.; Newgard, Christopher B.; Drujan, Doreen; Glass, David J.; Frederick, C. Brandon; Yoder, Bryan C.; Lalush, David S.; Patterson, Cam; Willis, Monte.

In: Molecular and Cellular Endocrinology, Vol. 413, 05.09.2015, p. 36-48.

Research output: Contribution to journalArticle

Rodríguez, JE, Liao, JY, He, J, Schisler, JC, Newgard, CB, Drujan, D, Glass, DJ, Frederick, CB, Yoder, BC, Lalush, DS, Patterson, C & Willis, M 2015, 'The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination', Molecular and Cellular Endocrinology, vol. 413, pp. 36-48. https://doi.org/10.1016/j.mce.2015.06.008
Rodríguez, Jessica E. ; Liao, Jie Ying ; He, Jun ; Schisler, Jonathan C. ; Newgard, Christopher B. ; Drujan, Doreen ; Glass, David J. ; Frederick, C. Brandon ; Yoder, Bryan C. ; Lalush, David S. ; Patterson, Cam ; Willis, Monte. / The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination. In: Molecular and Cellular Endocrinology. 2015 ; Vol. 413. pp. 36-48.
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