Syntaxin 4 protects islet β-cells from cytokine-induced senescence.

Area of Science:

• Endocrinology
• Cell Biology
• Immunology

Background:

• Type 1 diabetes (T1D) involves progressive loss of pancreatic beta cells, exacerbated by cytokine-induced senescence and the senescence-associated secretory phenotype (SASP).
• Syntaxin 4 (STX4), a t-SNARE protein, has demonstrated cytoprotective properties.
• Investigating STX4's role in mitigating beta cell senescence under diabetogenic stress is crucial for T1D therapeutic development.

Purpose of the Study:

• To determine if Syntaxin 4 (STX4) can mitigate beta cell senescence induced by diabetogenic stress.
• To explore the molecular mechanisms by which STX4 influences beta cell senescence and secretome.

Main Methods:

• Ectopic STX4 expression was induced in MIN6 cells, human islets, and murine islets, followed by senescence-inducing stress (cytokine and bleomycin treatment).
• Senescence markers (p21, γH2AX, nuclear Lamin B) were quantified in vitro and in vivo (non-obese diabetic mice).
• Single-cell RNA sequencing and conditioned-medium proteomics were performed to analyze STX4-dependent transcriptional and secretome changes.

Main Results:

• STX4 overexpression significantly reduced senescence markers (p21, γH2AX) in beta cells under stress.
• In vivo, STX4 induction in non-obese diabetic mice preserved nuclear Lamin B1 and reduced senescence markers, indicating a senoprotective effect.
• Transcriptomic and proteomic analyses revealed that STX4 represses senescence pathways and modifies the beta cell secretome, including enrichment of purine ribonucleotide metabolism proteins.

Conclusions:

• Syntaxin 4 (STX4) demonstrates a senoprotective effect on pancreatic beta cells against cytokine or bleomycin-induced senescence.
• Enhancing STX4 activity presents a potential therapeutic strategy for preserving functional beta cell mass in Type 1 diabetes.