RNF34 is a cold-regulated E3 ubiquitin ligase for PGC-1alpha and modulates brown fat cell metabolism
Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Carrier Proteins; Ubiquitin-Protein Ligases; Heat-Shock Proteins; Transcription Factors; Adipocytes, Brown
Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Genetics and Genomics
The transcriptional co-activator PGC-1alpha is a master regulator of energy metabolism and adaptive thermogenesis in the brown fat. PGC-1alpha is a short-lived protein, but the molecular components that control PGC-1alpha turnover and their functional importance in energy metabolism are largely unknown. Here we perform a luciferase-based overexpression screen and identify a Ring-finger-containing protein, RNF34, as a specific E3 ubiquitin ligase for PGC-1alpha. RNF34 is a nuclear protein that interacts with and ubiquitinates PGC-1alpha to promote its turnover. Interestingly, RNF34 binds to the C-terminal half of PGC-1alpha and targets it for degradation independent of the previously identified N-terminal phosphodegron motif. In brown fat cells, knockdown of RNF34 increases endogenous PGC-1alpha protein level, UCP1 expression and oxygen consumption, while the opposite effects are observed in brown fat cells ectopically expressing wild type RNF34, but not in cells expressing the ligase activity defective mutant. Moreover, cold exposure or beta3-adrenergic receptor signaling, conditions that induce PGC-1alpha expression, suppresses RNF34 expression in the brown fat, indicating a physiological relevance of this E3 ligase in thermogenesis. Our results reveal that RNF34 is a bona fide E3 ubiquitin ligase for PGC-1alpha and negatively regulates brown fat cell metabolism.
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Citation: Mol Cell Biol. 2011 Nov 7. Link to article on publisher's site