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Review
. 2021 Feb;1864(2):194626.
doi: 10.1016/j.bbagrm.2020.194626. Epub 2020 Aug 19.

GCN5 acetyltransferase in cellular energetic and metabolic processes

Beste Mutlu  1 , Pere Puigserver  2
Affiliations
Review

GCN5 acetyltransferase in cellular energetic and metabolic processes

Beste Mutlu et al. Biochim Biophys Acta Gene Regul Mech. 2021 Feb.

Abstract

General Control Non-repressed 5 protein (GCN5), encoded by the mammalian gene Kat2a, is the first histone acetyltransferase discovered to link histone acetylation to transcriptional activation [1]. The enzymatic activity of GCN5 is linked to cellular metabolic and energetic states regulating gene expression programs. GCN5 has a major impact on energy metabolism by i) sensing acetyl-CoA, a central metabolite and substrate of the GCN5 catalytic reaction, and ii) acetylating proteins such as PGC-1α, a transcriptional coactivator that controls genes linked to energy metabolism and mitochondrial biogenesis. PGC-1α is biochemically associated with the GCN5 protein complex during active metabolic reprogramming. In the first part of the review, we examine how metabolism can change GCN5-dependent histone acetylation to regulate gene expression to adapt cells. In the second part, we summarize the GCN5 function as a nutrient sensor, focusing on non-histone protein acetylation, mainly the metabolic role of PGC-1α acetylation across different tissues.

Keywords: Acetyl-CoA; Acetylation; GCN5; Glucose homeostasis; Metabolism; Mitochondria; PGC-1α.

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Conflict of interest statement

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. Acetyl-CoA production links metabolic state of the cell to histone acetylation by GCN5.
Acetyl-CoA is a central metabolite used as a substrate by HATs including GCN5. Upon nutrient deprivation, acetyl-CoA can be directed to the TCA cycle for energy production. When nutrients are in excess, acetyl-CoA is directed away from the mitochondria. Since there is no transporter for acetyl-CoA, it is first converted into citrate in mitochondria, which is shuttled to the cytosol. In the cytosol, ACL converts citrate back into acetyl-CoA, which becomes available to be used by GCN5 for histone acetylation.
Figure 2.
Figure 2.. Function and regulation of PGC-1α during nutrient sensing.
A) Transcriptional activity of PGC-1α is tightly linked to its acetylation status. GCN5 and PCAF were shown to acetylate PGC-1α, which decreases its activity. TIP60, p300 and SRC-1/3 are other acetyltransferases known to interact with PGC-1α, without any evidence that they influence the acetylation of PGC-1α. B) In the fed state, insulin signaling inactivates PGC-1α through the AKT pathway. In the fasted state, glucagon signaling induces PGC-1α via the CREB pathway. Activation of PGC-1α results in upregulation of its target genes which are involved in mitochondrial biogenesis, gluconeogenesis in the liver, and glucose uptake in other tissues.
Figure 3.
Figure 3.. An antidiabetic compound modulates PGC-1α acetylation by GCN5.
SR-18292 enhances interactions between GCN5 and PGC-1α, increases PGC-1α acetylation and inhibits PGC-1α activity. Increased interactions between GCN5 and PGC-1α reduce the interactions between PGC-1α and HNF4α, decreasing the co-activation of gluconeogenic target genes. Suppression of gluconeogenesis by SR-18292 provides beneficial effects in diabetic mouse models, including decreased fasting blood glucose and increased insulin sensitivity.
Figure 4.
Figure 4.. Transition from feeding to fasting conditions, as hepatic cells induce glucose production by turning on PGC-1α target genes.
In the fed state, GCN5 acetylates PGC-1α and its target genes remain inactive (left panel). During fasting, GCN5 forms a complex with PKA and CITED2 and gets phosphorylated by PKA. This leads to a conformational change and GCN5 starts to favor histones as a substrate instead of PGC-1α (middle panel). GCN5 promotes the activation of PGC-1α target genes by histone acetylation during fasting (right panel). These results demonstrate a dual role for GCN5 in inactivating PGC-1α in the fed state and activating PGC-1α target genes in the fasted state.
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