Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes
Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes
复制标题
DOI：
10.1074/jbc.m114.562355
复制
发表时间：
2014-06-06
影响因子：
4.8
通讯作者：
Liu, Ming
中科院分区：
文献类型：
--
作者：
Guo, Huan;Xiong, Yi;Liu, Ming
在胰岛素生物合成早期事件的缺陷中，胰岛素原错误折叠和内质网（ER）应激作为β细胞衰竭的原因引起了越来越多的关注。然而，尚未有研究解决前胰岛素原进入分泌途径的胞浆入口点的潜在缺陷。在这里，我们提供了第一个证据，证明前胰岛素原的低效易位（由其信号序列 n 区正电荷丢失引起）会导致 β 细胞衰竭和糖尿病。具体来说，我们发现，在靶向内质网膜后，与常染色体显性迟发性糖尿病相关的前胰岛素原信号肽（SP）突变体无法完全跨过内质网膜易位。新合成的未易位的前胰岛素原仍然与内质网膜密切相关，将其胰岛素原部分暴露于细胞质。未易位的前胰岛素原不是在 ER 中积累并诱导 ER 应激，而是在不同于高尔基复合体的核旁区室中积累，诱导热休克蛋白 70 (HSP70) 的表达，并促进 β 细胞死亡。恢复突变型前胰岛素原 SP 的 N 端正电荷可显着改善易位缺陷。这些发现不仅揭示了β细胞衰竭和糖尿病的新分子发病机制，而且还为分泌蛋白的SP n区正电荷的生理和病理意义提供了第一个证据。
Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of beta cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to beta cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes beta cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of beta cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins.