Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö 214-28, Sweden.
Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2312621121. doi: 10.1073/pnas.2312621121. Epub 2024 Feb 12.
One of the hallmarks of type 1 but also type 2 diabetes is pancreatic islet inflammation, associated with altered pancreatic islet function and structure, if unresolved. IL-1β is a proinflammatory cytokine which detrimentally affects β-cell function. In the course of diabetes, complement components, including the central complement protein C3, are deregulated. Previously, we reported high C3 expression in human pancreatic islets, with upregulation after IL-1β treatment. In the current investigation, using primary human and rodent material and CRISPR/Cas9 gene-edited β-cells deficient in C3, or producing only cytosolic C3 from a noncanonical in-frame start codon, we report a protective effect of C3 against IL-1β-induced β-cell death, that is attributed to the cytosolic fraction of C3. Further investigation revealed that intracellular C3 alleviates IL-1β-induced β-cell death, by interaction with and inhibition of Fyn-related kinase (FRK), which is involved in the response of β-cells to cytokines. Furthermore, these data were supported by increased β-cell death in vivo in a β-cell-specific C3 knockout mouse. Our data indicate that a functional, cytoprotective association exists between FRK and cytosolic C3.
1 型和 2 型糖尿病的特征之一是胰岛炎症，与胰岛功能和结构改变有关，如果不解决，就会发生这种情况。IL-1β 是一种促炎细胞因子，它会损害 β 细胞的功能。在糖尿病的过程中，补体成分，包括中央补体蛋白 C3，会失调。此前，我们报道了 C3 在人胰岛中的高表达，在 IL-1β 处理后上调。在目前的研究中，我们使用原代人和啮齿动物材料以及 CRISPR/Cas9 基因编辑的 C3 缺乏的 β 细胞或从非典型的框架内起始密码子产生仅具有细胞质 C3 的细胞，报告了 C3 对 IL-1β 诱导的 β 细胞死亡的保护作用，这归因于 C3 的细胞质部分。进一步的研究表明，细胞内 C3 通过与 Fyn 相关激酶（FRK）相互作用并抑制其活性，从而减轻 IL-1β 诱导的 β 细胞死亡，FRK 参与了 β 细胞对细胞因子的反应。此外，这些数据得到了在 β 细胞特异性 C3 敲除小鼠中体内 β 细胞死亡增加的支持。我们的数据表明，FRK 和细胞质 C3 之间存在功能性的、细胞保护的关联。
