title: RNF34 is a cold-regulated E3 ubiquitin ligase for PGC-1α and modulates brown fat cell metabolism.
abstract: The transcriptional coactivator PGC-1α is a master regulator of energy metabolism and adaptive thermogenesis in the brown fat cell. PGC-1α is a short-lived protein, and the molecular components that control PGC-1α 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-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 independently of the previously identified N-terminal phosphodegron motif. In brown fat cells, knockdown of RNF34 increases the endogenous PGC-1α 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 β3-adrenergic receptor signaling, conditions that induce PGC-1α 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-1α and negatively regulates brown fat cell metabolism.
authors: Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Ping
authors: P
authors: Wei
authors: Dongning
authors: D
authors: Pan
authors: Chunxiao
authors: C
authors: Mao
authors: Yong-Xu
authors: YX
authors: Wang
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003080:Cold Temperature; D004734:Energy Metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011485:Protein Binding; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C461219:RNF34 protein, human; D015534:Trans-Activators; D044767:Ubiquitin-Protein Ligases