SREBP1c is regulated by E3 ligase RNF20/BRE1A upon hormonal changes

Abstract

Sterol regulatory element binding protein 1c (SREBP1c) is a key transcription factor to regulate de novo lipogenesis. However, molecular mechanisms involved in suppression of SREBP1c are largely unknown. In this study, we reveal that SREBP1c is negatively regulated by ubiquitination upon fasting signals. To better understand which factors are involved in ubiquitination of SREBP1c, we take advantages of affinity purification and mass spectrometry. In this analysis, RNF20/BRE1A is identified as a novel SREBP1c E3 ligase. Here we show that RNF20/BRE1A binds to and ubiquitinates SREBP1c, leading to its degradation. Previously, it has been well established that PKA signaling is activated by fasting signals. Interestingly, we find out that PKA activator such as forskolin enhances expression of RNF20/BRE1A and stimulates ubiquitination of SREBP1c via RNF20/BRE1A. In accordance with these, RNF20/BRE1A negatively regulates the transcriptional activity of SREBP1c and expression of SREBP1c target genes. In contrast, knockdown of RNF20/BRE1A increases expression of SREBP1c and lipogenic genes. Taken together, these data suggest that RNF20/BRE1A would be a negative regulator of lipogenesis through degradation of SREBP1c upon fasting.J. H. Lee was supported by Hi Seoul Science (Humanities) Fellowship funded by Seoul Scholarship Foundation.