INS1-EGFP-L10a stable cell lines treated with Thapsigargin

When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this “Terminal UPR”. TXNIP becomes rapidly induced by hyperactivated IRE1a, an ER bifunctional kinase/endoribonuclease (RNase). IRE1a controls TXNIP mRNA stability by reducing levels of a TXNIP destabilizing micro-RNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing Caspase-1 cleavage and interleukin 1b (IL-1b) secretion. Txnip gene deletion reduces pancreatic b-cell death during ER stress, and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1a RNase inhibitors suppress TXNIP production to block IL-1b secretion. In summary, the IRE1a-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death, and may be targeted to develop new treatments for degenerative diseases driven by ER stress.当未折叠蛋白在内质网（endoplasmic reticulum, ER）中累积至无法纠正的高水平时，被称为未折叠蛋白反应（unfolded protein response, UPR）的细胞内信号通路会过度激活，进而引发程序性细胞死亡。我们的研究发现，硫氧还蛋白相互作用蛋白（thioredoxin-interacting protein, TXNIP）是这一“终末未折叠蛋白反应”中的关键节点。TXNIP会被过度激活的IRE1α快速诱导表达，而IRE1α是一种兼具激酶与核糖核酸内切酶（endoribonuclease, RNase）活性的双功能蛋白。IRE1α通过降低可使TXNIP mRNA不稳定的微RNA miR-17的水平，调控TXNIP mRNA的稳定性。反之，升高的TXNIP蛋白会激活NLRP3炎症小体，引发半胱天冬氨酸蛋白酶-1（Caspase-1）的切割以及白细胞介素1β（interleukin 1β, IL-1β）的分泌。敲除Txnip基因可减轻内质网应激状态下的胰岛β细胞死亡，并抑制秋田小鼠（Akita小鼠）中由胰岛素原错误折叠所引发的糖尿病。最后，小分子IRE1α核糖核酸内切酶抑制剂可通过抑制TXNIP的产生来阻断IL-1β的分泌。综上，IRE1α-TXNIP通路在终末未折叠蛋白反应中介导无菌性炎症与程序性细胞死亡，有望作为靶点开发内质网应激驱动的退行性疾病的新型治疗策略。