Med14 phosphorylation shapes genomic response to GLP-1 agonists

TL;DR

This study shows how GLP-1 agonists improve beta cell function by phosphorylating Med14, a key transcriptional coactivator, leading to better insulin secretion and cell viability.

Contribution

The novel finding is that Med14 phosphorylation at Ser983 is essential for GLP-1 agonist-induced genomic responses in beta cells.

Findings

Phosphorylation of Med14 at Ser983 is required for GLP-1 agonist effects on gene expression in beta cells.

Mutation of Med14 at Ser983 disrupts CREB-mediated activation of beta cell-specific enhancers.

Med14 phosphorylation leads to improved beta cell viability and insulin secretion.

Abstract

Stable GLP-1 agonists like Exendin-4 and Ozempic have become a mainstay for treatment of type II diabetes; these peptides enhance insulin secretion and improve beta cell viability in part through sustained activation of the cAMP-CREB pathway. The long-term benefits of GLP-1 receptor agonists appear to reflect the genomic adaptation of beta cells to elevated levels of circulating glucose and lipids in the blood. We found that exposure of pancreatic islet beta cells to GLP-1 receptor agonist promotes phosphorylation of Med14, a subunit of the mediator transcriptional complex. As mutation of Med14 at this phosphorylation site blocks induction of GLP-1-responsive genes, our studies suggest how a general coactivator can promote the selective induction of metabolic programs in response to circulating hormones.

Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

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