ER-associated degradation is required for the maintenance of beta cell identity via TGFbeta signaling

Beta cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying beta cell loss in type 2 diabetes (T2D); however, the molecular drivers underlying such events remain largely unclear. Here, by performing a side-by-side comparison of mice carrying beta cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy, we report that while autophagy appears necessary for beta cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex is required for the maintenance of beta cell maturation and identity. Notably, SEL1L expression is significantly reduced in human T2D islets compared to healthy human islets. At the single cell level, we demonstrate that Sel1L deficiency is not associated with beta cell loss, but rather loss of beta cell identity. Mechanistically, we find that Sel1L-Hrd1 ERAD controls beta cell identity via TGFbeta signaling, in part by mediating the degradation of TGF-beta receptor 1 (TGFbetaRI). Inhibition of TGFbeta signaling in Sel1L-deficient beta cells augments the expression of beta cell maturation markers and increases the total insulin content. Our data reveal profound but distinct pathogenic effects of two major proteolytic pathways in beta cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control. Gene expression was profiled in pancreatic islets isolated from 5-week-old wildtype and beta cell-specific Sel1L-deficient mice.β细胞凋亡与去分化是2型糖尿病（T2D）中β细胞丢失的两大备受争议的潜在机制，但此类事件的分子驱动因素仍未完全阐明。本研究通过对携带β细胞特异性内质网（ER）相关降解（ERAD）与自噬基因敲除的小鼠进行平行对照分析，发现尽管自噬对β细胞存活似乎不可或缺，但高度保守的Sel1L-Hrd1内质网相关降解蛋白复合物却是维持β细胞成熟状态与细胞身份所必需的。值得注意的是，与健康人类胰岛相比，2型糖尿病患者的人类胰岛中SEL1L的表达水平显著降低。在单细胞层面，我们证实Sel1L缺失并不会导致β细胞丢失，而是引发β细胞身份的丧失。从机制上看，Sel1L-Hrd1内质网相关降解复合物通过转化生长因子β（TGFβ）信号通路调控β细胞身份，其部分途径是介导转化生长因子β受体1（TGFβRI）的降解。在Sel1L缺失的β细胞中抑制TGFβ信号通路，可增强β细胞成熟标志物的表达，并提升总胰岛素含量。本研究揭示了两条主要蛋白水解通路在β细胞中发挥的深刻且迥异的致病作用，为靶向不同蛋白质质量控制机制的治疗策略提供了全新的研究框架。本研究对5周龄野生型小鼠及β细胞特异性Sel1L敲除小鼠的分离胰岛进行了基因表达谱分析。