Regulation of STAT1 signalling in human pancreatic β-cells by the lysine deacetylase, HDAC6; a new therapeutic opportunity in type 1 diabetes?

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posted on 2024-06-13, 15:05 authored by Kaiyven Afi Leslie, Christiana Lekka, Sarah J. Richardson, Mark A. Russell, Noel G. Morgan

Abstract

Type 1 diabetes arises from the selective destruction of pancreatic β-cells by autoimmune mechanisms and intracellular pathways driven by Janus (JAK)-kinase mediated STAT isoforms (especially STAT1 & STAT2) are implicated as mediators of β-cell demise. Despite this, the molecular mechanisms that regulate JAK-STAT signalling in β-cells during the autoimmune attack remain only partially disclosed and the factors acting to antagonise pro-inflammatory STAT1 signalling are uncertain. We have recently implicated Signal Regulatory Protein (SIRP)-α in promoting β-cell viability in the face of ongoing islet autoimmunity and now reveal that this protein controls the availability of a cytosolic lysine deacetylase, HDAC6, whose activity regulates the phosphorylation and activation of STAT1. We provide evidence that STAT1 serves as a substrate for HDAC6 in β-cells and that sequestration of HDAC6 by SIRPα in response to anti-inflammatory cytokines (such as interleukin-13) leads to increased STAT1 acetylation. This then impairs the ability of STAT1 to promote gene transcription in response to pro-inflammatory cytokines including interferon-gamma (IFNγ). We further find that SIRPα is lost from the β-cells of subjects with recent-onset type 1 diabetes under conditions when HDAC6 is retained and STAT1 levels are increased. On this basis, we report a previously unrecognised role for cytokine-induced regulation of STAT1 acetylation in the control of β-cell viability and propose that targeted inhibition of HDAC6 activity may represent a novel therapeutic modality to promote β-cell viability in the face of active islet autoimmunity.

Article Highlights

· Signal regulatory protein-alpha (SIRPα) is present in human islet cells but its levels decline in β-cells in type 1 diabetes.

· Decreases in SIRPα expression are associated with a reduction in the viability of cultured β-cells.

· Immunoprecipitation of β-cell SIRPα reveals a direct interaction with the lysine deacetylase, HDAC6.

· Sequestration of HDAC6 by SIRPα results in increased acetylation, reduced phosphorylation and impaired activation of STAT1 during exposure of β-cells to IFNγ.

· Pharmacological targeting of HDAC6 might yield improvements in β-cell viability during progression to type 1 diabetes.