Regulation of STAT1 Signaling in Human Pancreatic β-Cells by the Lysine Deacetylase HDAC6: A New Therapeutic Opportunity in Type 1 Diabetes?

• Published in: Diabetes (New York, N.Y.) Vol. 73; no. 9; pp. 1473 - 1485
• Main Authors: Leslie, Kaiyven Afi, Lekka, Christiana, Richardson, Sarah J, Russell, Mark A, Morgan, Noel G
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2024
• Subjects: Acetylation; Acetylation - drug effects; Autoimmunity; Beta cells; Cell activation; Cell viability; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; Histone Deacetylase 6 - genetics; Histone Deacetylase 6 - metabolism; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Inflammation; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Intracellular signalling; Isoforms; Janus kinase; Kinases; Lysine; Molecular modelling; Pancreas; Phosphorylation; Phosphorylation - drug effects; Signal Transduction - drug effects; Stat1 protein; STAT1 Transcription Factor - metabolism; Stat2 protein; γ-Interferon
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db24-0008

Type 1 diabetes arises from the selective destruction of pancreatic β-cells by autoimmune mechanisms, and intracellular pathways driven by Janus kinase (JAK)-mediated phosphorylation of STAT isoforms (especially STAT1 and STAT2) are implicated as mediators of β-cell demise. Despite this, the molecular mechanisms that regulate JAK-STAT signaling in β-cells during the autoimmune attack remain only partially disclosed, and the factors acting to antagonize proinflammatory STAT1 signaling are uncertain. We have recently implicated signal regulatory protein α (SIRPα) in promoting β-cell viability in the face of ongoing islet autoimmunity and have now revealed 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 (e.g., IL-13) leads to increased STAT1 acetylation. This then impairs the ability of STAT1 to promote gene transcription in response to proinflammatory cytokines, including interferon-γ. We further found 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 unrecognized 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.