Lipson Kathryn L, Ghosh Rajarshi, Urano Fumihiko
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
PLoS One. 2008 Feb 20;3(2):e1648. doi: 10.1371/journal.pone.0001648.
The endoplasmic reticulum (ER) is a cellular compartment for the biosynthesis and folding of newly synthesized secretory proteins such as insulin. Perturbations to ER homeostasis cause ER stress and subsequently activate cell signaling pathways, collectively known as the Unfolded Protein Response (UPR). IRE1alpha is a central component of the UPR. In pancreatic beta-cells, IRE1alpha also functions in the regulation of insulin biosynthesis.
Here we report that hyperactivation of IRE1alpha caused by chronic high glucose treatment or IRE1alpha overexpression leads to insulin mRNA degradation in pancreatic beta-cells. Inhibition of IRE1alpha signaling using its dominant negative form prevents insulin mRNA degradation. Islets from mice heterozygous for IRE1alpha retain expression of more insulin mRNA after chronic high glucose treatment than do their wild-type littermates.
CONCLUSIONS/SIGNIFICANCE: These results reveal a role of IRE1alpha in insulin mRNA expression under ER stress conditions caused by chronic high glucose. The rapid degradation of insulin mRNA could provide immediate relief for the ER and free up the translocation machinery. Thus, this mechanism would preserve ER homeostasis and help ensure that the insulin already inside the ER can be properly folded and secreted. This adaptation may be crucial for the maintenance of beta-cell homeostasis and may explain why the beta-cells of type 2 diabetic patients with chronic hyperglycemia stop producing insulin in the absence of apoptosis. This mechanism may also be involved in suppression of the autoimmune type 1 diabetes by reducing the amount of misfolded insulin, which could be a source of "neo-autoantigens."
内质网（ER）是用于新合成的分泌蛋白（如胰岛素）生物合成和折叠的细胞区室。内质网稳态的扰动会导致内质网应激，并随后激活细胞信号通路，统称为未折叠蛋白反应（UPR）。肌醇需求酶1α（IRE1α）是UPR的核心组成部分。在胰腺β细胞中，IRE1α还在胰岛素生物合成的调节中发挥作用。
在此我们报告，慢性高糖处理或IRE1α过表达导致的IRE1α过度激活会导致胰腺β细胞中胰岛素mRNA降解。使用其显性负性形式抑制IRE1α信号传导可防止胰岛素mRNA降解。与野生型同窝小鼠相比，IRE1α杂合子小鼠的胰岛在慢性高糖处理后保留更多胰岛素mRNA的表达。
结论/意义：这些结果揭示了IRE1α在慢性高糖引起的内质网应激条件下对胰岛素mRNA表达的作用。胰岛素mRNA的快速降解可为内质网提供即时缓解，并释放转运机制。因此，这种机制将维持内质网稳态，并有助于确保内质网内已有的胰岛素能够正确折叠和分泌。这种适应性对于维持β细胞稳态可能至关重要，并且可以解释为什么患有慢性高血糖的2型糖尿病患者的β细胞在没有凋亡的情况下停止产生胰岛素。这种机制也可能通过减少错误折叠的胰岛素量（这可能是“新自身抗原”的来源）参与对自身免疫性1型糖尿病的抑制。
