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

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:413

Article

Rodriguez, Jessica E.¹  Liao, Jie-Ying¹  He, Jun²  Schisler, Jonathan C.³  Newgard, Christopher B.^4,5  Drujan, Doreen⁶  Glass, David J.⁶  Frederick, C. Brandon⁷  Yoder, Bryan C.⁷  Lalush, David S.⁷  Patterson, Cam^3,8  Willis, Monte S.^1,3 

[1] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[2] Ningxia Med Univ, Gen Hosp, Ningxia, Peoples R China

[3] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27599 USA

[4] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC USA

[5] Duke Univ, Med Ctr, Div Endocrinol Metab & Nutr, Durham, NC USA

[6] Novartis Inst Biomed Res, Cambridge, MA USA

[7] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA

[8] Presbyterian Hosp, Weill Cornell Med Ctr, New York, NY USA

关键词: Cardiomyocyte;    Peroxisome proliferator-activated receptor alpha;    Fatty acid metabolism;    Cardiac metabolism;    Monoubiquitination;    Muscle ring finger-1;   

DOI  :  10.1016/j.mce.2015.06.008

来源: Elsevier

【 摘 要 】

The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) alpha 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 PPAR alpha, but not PPAR beta/delta or PPAR gamma in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPAR alpha activity and acyl-carnitine intermediates, while MuRF1-/- hearts exhibited increased PPAR alpha activity and acyl-camitine intermediates. MuRF1 directly interacts with PPAR alpha, monoubiquitinates 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 PPARa, 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 PPAR alpha, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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