自噬
脂毒性
ULK1
磷酸化
细胞生物学
激酶
β细胞
程序性细胞死亡
化学
癌症研究
小岛
内分泌学
医学
生物
胰岛素
内科学
生物化学
细胞凋亡
胰岛素抵抗
安普克
蛋白激酶A
作者
Yuting Lu,Jun‐Yu Xu,Y Li,Ruo-Ran Wang,Chengqiu Dai,Bingqian Zhang,Xinwen Zhang,Lei Xu,Yadong Tao,Ming Han,Ren Guo,Qingqian Wu,Linshi Wu,Zhuo-Xian Meng,Minjia Tan,Jingya Li
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2024-02-07
卷期号:16 (733)
标识
DOI:10.1126/scitranslmed.ade8647
摘要
Impeded autophagy can impair pancreatic β cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic β cells protected β cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51–like autophagy activating kinase 1 (ULK1) at Ser 56 , which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic β cells upon metabolic challenge, which offers a potential target to protect β cell function in T2D.
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