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[摘要]：The transcriptional coactivator PGC-1 alpha is a master regulator of energy metabolism and adaptive thermogenesis in the brown fat cell. PGC-1 alpha is a short-lived protein, and the molecular components that control PGC-1 alpha turnover and their functional importance in energy metabolism are largely unknown. Here we performed a luciferase-based overexpression screen and identified a Ring-finger-containing protein, RNF34, as a specific E3 ubiquitin ligase for PGC-1 alpha. RNF34 is a nuclear protein that interacts with and ubiquitinates PGC-1 alpha to promote its turnover. Interestingly, RNF34 binds to the C-terminal half of PGC-1 alpha and targets it for degradation independently of the previously identified N-terminal phosphodegron motif. In brown fat cells, knockdown of RNF34 increases the endogenous PGC-1 alpha protein level, uncoupling protein 1 (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 and beta 3-adrenergic receptor signaling, conditions that induce PGC-1 alpha expression, suppress RNF34 expression in the brown fat cell, indicating a physiological relevance of this E3 ligase in thermogenesis. Our results reveal that RNF34 is a bona fide E3 ubiquitin ligase for PGC-1 alpha and negatively regulates brown fat cell metabolism. |
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