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Muscle Ring Finger‐1 (MuRF1) inhibits cardiac PPARα activity by directing its nuclear export and not its degradation
Author(s) -
Rodríguez Jessica E.,
Li Luge,
Willis Monte S
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1104.2
Subject(s) - nuclear export signal , peroxisome proliferator activated receptor , chemistry , ring finger , ubiquitin ligase , microbiology and biotechnology , transcription factor , intracellular , nuclear transport , in vivo , nuclear receptor , receptor , ubiquitin , biochemistry , cell nucleus , biology , cytoplasm , gene
Previously we demonstrated that the ubiquitin ligase Muscle Ring Finger‐1 (MuRF1) interacts with and inhibits the activity of the PPARα transcription factor in vitro , resulting in the inhibition of fatty acid oxidation. The mechanism of how MuRF1 regulates PPARα activity remains unknown. In these studies, we determined how MuRF1 might be regulating intracellular PPARα localization using confocal microscopy. Increasing MuRF1 expression using adenovirus constructs (Ad.MuRF1) in HL‐1 cardiomyocytes resulted in a nuclear clearance of PPARα from ~80% of cells, compared to Ad. GFP controls that had <1% of nuclei without PPARα present. This nuclear clearance of PPARα resulted in an 80% decrease in PPARα activity. To examine if nuclear export played a role in MuRF1's ability to inhibit PPARα activity; HL‐1 cardiomyocytes were treated with Leptomycin B, an inhibitor of nuclear export, in the presence or absence of increasing MuRF1 expression. We identified that nuclear export was necessary for MuRF1 to inhibit PPARα activity, and that MuRF1 translocates into the nucleus. Consistent with these findings, MuRF1−/− and MuRF1 Tg+ hearts indicate no changes in PPARα expression, despite enhanced and decreased PPARα activity, respectively, > in vivo . These findings suggest MuRF1's critical role in regulating cardiac metabolism by its direct interactions with PPARα to direct its nuclear export. Supported by NIH R01HL104129.