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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Rodríguez, JE; Liao, J-Y; He, J; Schisler, JC; Newgard, CB; Drujan, D; Glass, DJ; Frederick, CB; Yoder, BC; Lalush, DS; Patterson, C; Willis, MS

Published Date

  • September 2015

Published In

Volume / Issue

  • 413 /

Start / End Page

  • 36 - 48

PubMed ID

  • 26116825

Electronic International Standard Serial Number (EISSN)

  • 1872-8057

International Standard Serial Number (ISSN)

  • 0303-7207

Digital Object Identifier (DOI)

  • 10.1016/j.mce.2015.06.008

Language

  • eng