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.
Signal regulatory protein α (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 interferon-γ.
Pharmacological targeting of HDAC6 might yield improvements in β-cell viability during progression to type 1 diabetes.
This article contains supplementary material online at https://doi.org/10.2337/figshare.26018608.
