Role of transcription factor acetylation in the regulation of metabolic homeostasis

Abstract

Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.

Keywords: metabolic homeostasis; post-translational modification; transcription factor; type 2 diabetes mellitus.

Figure 1

Functional consequences of acetylation of transcription factors. Ac, acetyl group; K, lysine residue

Figure 2

Role of transcription factor acetylation on the regulation of glucose. (A) Effect of FOXO1 and CREB acetylation on the carbohydrate metabolism. Acetylation of FOXO1 is balanced by SIRT1 and CBP/p300. Once acetylated, 14-3-3 binds to FOXO1, and localizes to cytosol. The 14-3-3-FOXO1 complex is subjected to proteosomal degradation in cytosol. Deacetylated form of FOXO1 binds to IRE and transactivates glycolytic genes or gluconeogenic genes in a negative or a positive way, respectively. Acetylated form of CREB transactivates gluconeogenic gene expression by binding to CRE in the gluconeogenic genes. Acetylation of CREB is promoted when CREB is phosphorylated. (B) Effect of transcription factor acetylation on the expression of lipogenic genes. Deacetylated form of FOXO1 downregulates adipogenic gene expression by binding to IRE of respective genes. FOXA2 is acetylated by p300 and upregulates expression of genes involved in β-oxidation and ketogenesis. Deacetylated form of FOXA2 is subjected to proteosomal degradation. SREBP family is also acetylated by CBP/p300. Acetylated form of SREBPs upregulates lipogeneic gene expression. Deacetylated form of SREBPs undergo proteasomal degradation. Acetylated form of ChREBP by p300 upregulates gene expression of lipogenic genes. Deacetylated form of ChREBP is phosphorylated by PKA, which promotes binding of 14-3-3, resulting in cytosolic localization. Acetylation of C/EBPβ is balanced by GCN5 and HDAC1. Acetyl-C/EBPβ upregulates adipogenic gene expression. Ac, acetyl group; P, phosphorylation; Ub, ubiquitination; IRE, insulin-response element; CRE, cAMP-response element; PKA, protein kinase A; SRE, SREBP response element; PP2a, protein phosphatase 2a; CRM1, chromosome region maintenance 1 protein