Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell Metab. 2012 Aug 8;16(2):265-73. doi: 10.1016/j.cmet.2012.07.005.
Recent clinical and experimental evidence suggests that endoplasmic reticulum (ER) stress contributes to the life-and-death decisions of β cells during the progression of type 1 and type 2 diabetes. Although crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death, a key molecule connecting ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP) is a critical signaling node that links ER stress and inflammation. TXNIP is induced by ER stress through the PERK and IRE1 pathways, induces IL-1β mRNA transcription, activates IL-1β production by the NLRP3 inflammasome, and mediates ER stress-mediated β cell death. Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome.
最近的临床和实验证据表明，内质网（ER）应激在 1 型和 2 型糖尿病的进展过程中，对β细胞的生死决策起着重要作用。虽然炎症和 ER 应激之间的相互作用已被认为在β细胞功能障碍和死亡中起重要作用，但尚未确定将 ER 应激与炎症联系起来的关键分子。在这里，我们报告硫氧还蛋白相互作用蛋白（TXNIP）是连接 ER 应激和炎症的关键信号节点。TXNIP 通过 PERK 和 IRE1 途径被 ER 应激诱导，诱导 IL-1β mRNA 转录，激活 NLRP3 炎性体产生 IL-1β，并介导 ER 应激介导的β细胞死亡。总的来说，我们的研究结果表明，TXNIP 是糖尿病和 ER 应激相关人类疾病（如 Wolfram 综合征）的一个潜在治疗靶点。
