CREB-Regulated Transcriptional Coactivator 2 Proteome Landscape is Modulated by SREBF1

• Published in: Molecular & cellular proteomics Vol. 22; no. 10; p. 100637
• Main Authors: Lim, Jae Min, Anwar, Muhammad Ayaz, Han, Hye-Sook, Koo, Seung-Hoi, Kim, Kwang Pyo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2023; American Society for Biochemistry and Molecular Biology
• Subjects: coregulation; mass spectrometry; metabolism; PPI; STRING; CRTC; DRP; DPP; HFD; PPI; GBE; coregulation; ACACA; DAP; CREB; SPIA; TG; PPAR; DAcP; FASN; mass spectrometry; STRING; PCK; metabolism; TMT; log2FC; SREBF; BCAA; LPPI
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1016/j.mcpro.2023.100637

cAMP response element-binding protein (CREB) regulated transcriptional coactivator 2 (CRTC2) is a critical transcription factor that maintains glucose homeostasis by activating CREB. Energy homeostasis is maintained through multiple pathways; therefore, CRTC2 may interact with other transcription factors, particularly under metabolic stress. CRTC2 liver-specific KO mice were created, and the global proteome, phosphoproteome, and acetylome from liver tissue under high-fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry and bioinformatics analysis. Differentially regulated proteins (DRPs) were enriched in metabolic pathways, which were subsequently corroborated through animal experiments. The consensus DRPs from these datasets were used as seed proteins to generate a protein-protein interaction network using STRING, and GeneMANIA identified fatty acid synthase as a mutually relevant protein. In an additional local-protein-protein interaction analysis of CRTC2 and fatty acid synthase with DRPs, sterol regulatory element binding transcription factor 1 (SREBF1) was the common mediator. CRTC2-CREB and SREBF1 are transcription factors, and DNA-binding motif analysis showed that multiple CRTC2-CREB–regulated genes possess SREBF1-binding motifs. This indicates the possible induction by the CRTC2–SREBF1 complex, which is validated through luciferase assay. Therefore, the CRTC2–SREBF1 complex potentially modulates the transcription of multiple proteins that fine-tune cellular metabolism under metabolic stress. [Display omitted] •Global proteome analysis of CRTC2LKO revealed changes in metabolic-related pathways.•Animal model also replicated altered glucose, fat deposits, and TG levels.•Computational analysis showed that the altered metabolism is influenced by SREBF1.•Knockout and luciferase validated the cooperation of CRTC2 and SREBF1 in metabolism. CRTC2 (with CREB1) in glucose metabolism is well studied; however, further studies are required to delineate the metabolic regulatory aspects. Here, using various biochemical and computational tools, it has been identified that CRTC2 along with SREBF1 regulates targeted genes to fine-tune the metabolic response under various conditions. This should further highlight the tight regulation of glucose metabolism and could be therapeutically used for various diseases.