Wei P, Pan D, Mao C, Wang YX

The transcriptional co-activator PGC-1α is a master regulator of energy metabolism and adaptive thermogenesis in the brown fat. PGC-1α is a short-lived protein, but the molecular components that control PGC-1α turnover and their functional importance in energy metabolism are largely unknown. Here we perform a luciferase-based overexpression screen and identify ...

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a Ring-finger-containing protein, RNF34, as a specific E3 ubiquitin ligase for PGC-1α. RNF34 is a nuclear protein that interacts with and ubiquitinates PGC-1α to promote its turnover. Interestingly, RNF34 binds to the C-terminal half of PGC-1α and targets it for degradation independent of the previously identified N-terminal phosphodegron motif. In brown fat cells, knockdown of RNF34 increases endogenous PGC-1α 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 β3-adrenergic receptor signaling, conditions that induce PGC-1α 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-1α and negatively regulates brown fat cell metabolism.

Date: Nov. 07, 2011

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