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The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch

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ABSTRACT

Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon–cAMP–protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α–mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.

No MeSH data available.


Related in: MedlinePlus

Model for regulation of hepatic gluconeogenesis by the GCN5-CITED2-PKA signalling module through a cAMP-induced substrate switch of GCN5.(left) In the fed state, the GCN5-CITED2-PKA signalling module is not assembled as a result of the low level of CITED2 expression maintained in the absence of glucagon signalling and the insulin-induced inhibition of GCN5-CITED2 interaction. GCN5 is not phosphorylated at Ser275 and therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and consequent suppression of gluconeogenic gene transcription. (middle) In the fasted state or diabetes, glucagon-cAMP signalling increases the expression of CITED2 and GCN5 and thereby promotes formation of the GCN5-CITED2-PKA signalling module, within which PKA activated by cAMP phosphorylates GCN5 at Ser275. (right) Phosphorylation of GCN5 induces a substrate switch from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program. AT, acetyltransferase.
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f10: Model for regulation of hepatic gluconeogenesis by the GCN5-CITED2-PKA signalling module through a cAMP-induced substrate switch of GCN5.(left) In the fed state, the GCN5-CITED2-PKA signalling module is not assembled as a result of the low level of CITED2 expression maintained in the absence of glucagon signalling and the insulin-induced inhibition of GCN5-CITED2 interaction. GCN5 is not phosphorylated at Ser275 and therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and consequent suppression of gluconeogenic gene transcription. (middle) In the fasted state or diabetes, glucagon-cAMP signalling increases the expression of CITED2 and GCN5 and thereby promotes formation of the GCN5-CITED2-PKA signalling module, within which PKA activated by cAMP phosphorylates GCN5 at Ser275. (right) Phosphorylation of GCN5 induces a substrate switch from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program. AT, acetyltransferase.

Mentions: Our data show that, in the fasted state, glucagon-cAMP signalling increases the expression of CITED2 (ref. 20) and GCN5 as well as promotes the formation of a GCN5-CITED2-PKA signalling module. Within this module, PKA activated by cAMP phosphorylates GCN5 at Ser275 (with the phosphorylation of other PKA substrates such as CREB, VASP and IP3R being unaffected), resulting in a switch in the substrate preference of GCN5 from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas the activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program (Fig. 10). In the fed state, attenuation of glucagon signalling leads to downregulation of CITED2 and GCN5 expression, whereas insulin signalling inhibits GCN5-CITED2 interaction20, resulting in disruption of the GCN5-CITED2-PKA signalling module. In this condition, phosphorylation of GCN5 at Ser275 is inhibited and GCN5 therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and the consequent suppression of gluconeogenic gene transcription.


The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch
Model for regulation of hepatic gluconeogenesis by the GCN5-CITED2-PKA signalling module through a cAMP-induced substrate switch of GCN5.(left) In the fed state, the GCN5-CITED2-PKA signalling module is not assembled as a result of the low level of CITED2 expression maintained in the absence of glucagon signalling and the insulin-induced inhibition of GCN5-CITED2 interaction. GCN5 is not phosphorylated at Ser275 and therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and consequent suppression of gluconeogenic gene transcription. (middle) In the fasted state or diabetes, glucagon-cAMP signalling increases the expression of CITED2 and GCN5 and thereby promotes formation of the GCN5-CITED2-PKA signalling module, within which PKA activated by cAMP phosphorylates GCN5 at Ser275. (right) Phosphorylation of GCN5 induces a substrate switch from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program. AT, acetyltransferase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5121418&req=5

f10: Model for regulation of hepatic gluconeogenesis by the GCN5-CITED2-PKA signalling module through a cAMP-induced substrate switch of GCN5.(left) In the fed state, the GCN5-CITED2-PKA signalling module is not assembled as a result of the low level of CITED2 expression maintained in the absence of glucagon signalling and the insulin-induced inhibition of GCN5-CITED2 interaction. GCN5 is not phosphorylated at Ser275 and therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and consequent suppression of gluconeogenic gene transcription. (middle) In the fasted state or diabetes, glucagon-cAMP signalling increases the expression of CITED2 and GCN5 and thereby promotes formation of the GCN5-CITED2-PKA signalling module, within which PKA activated by cAMP phosphorylates GCN5 at Ser275. (right) Phosphorylation of GCN5 induces a substrate switch from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program. AT, acetyltransferase.
Mentions: Our data show that, in the fasted state, glucagon-cAMP signalling increases the expression of CITED2 (ref. 20) and GCN5 as well as promotes the formation of a GCN5-CITED2-PKA signalling module. Within this module, PKA activated by cAMP phosphorylates GCN5 at Ser275 (with the phosphorylation of other PKA substrates such as CREB, VASP and IP3R being unaffected), resulting in a switch in the substrate preference of GCN5 from PGC-1α to histone H3 and a consequent increase in H3K9 acetylation and the deacetylation-mediated activation of PGC-1α at gluconeogenic gene promoters. The increase in the amount of H3K9ac promotes further epigenetic changes and the recruitment of transcriptional regulators required for initiation of gene transcription, whereas the activated PGC-1α functions as a co-activator for gluconeogenic transcription factors such as FoxO1 and HNF-4α. These two effects act cooperatively to activate the gluconeogenic program (Fig. 10). In the fed state, attenuation of glucagon signalling leads to downregulation of CITED2 and GCN5 expression, whereas insulin signalling inhibits GCN5-CITED2 interaction20, resulting in disruption of the GCN5-CITED2-PKA signalling module. In this condition, phosphorylation of GCN5 at Ser275 is inhibited and GCN5 therefore acetylates PGC-1α rather than histone H3, resulting in inactivation of PGC-1α and the consequent suppression of gluconeogenic gene transcription.

View Article: PubMed Central - PubMed

ABSTRACT

Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon–cAMP–protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α–mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.

No MeSH data available.


Related in: MedlinePlus