DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition
文献类型：期刊论文
| 作者 | Lu, Yuting5; Xu, Junyu5,6; Li, Yufeng5; Wang, Ruoran1,7,8; Dai, Chengqiu2,5,8; Zhang, Bingqian2,5; Zhang, Xinwen5; Xu, Lei5,6; Tao, Yunhua5; Han, Ming5 |
| 刊名 | SCIENCE TRANSLATIONAL MEDICINE
 |
| 出版日期 | 2024-02-07 |
| 卷号 | 16期号:733页码:16 |
| ISSN号 | 1946-6234 |
| DOI | 10.1126/scitranslmed.ade8647 |
| 通讯作者 | Wu, Linshi(jyli@simm.ac.cn) ; Meng, Zhuoxian(mjtan@simm.ac.cn) ; Tan, Minjia(zxmeng@zju.edu.cn) ; Li, Jingya(wulinshirenji@163.com) |
| 英文摘要 | Impeded autophagy can impair pancreatic beta 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 beta cells protected beta 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 beta cells upon metabolic challenge, which offers a potential target to protect beta cell function in T2D. |
| WOS关键词 | PROTEIN-KINASE ; DAP-KINASE ; BECLIN 1 ; MITOCHONDRIA ; APOPTOSIS ; RNA ; UBIQUITYLATION ; LIPOTOXICITY ; HOMEOSTASIS ; DERIVATIVES |
| 资助项目 | National Natural Science Foundation of China[92057116] ; National Natural Science Foundation of China[81673493] ; National Natural Science Foundation of China[22225702] ; National Natural Science Foundation of China[92153302] ; National Natural Science Foundation of China[32071432] ; National Natural Science Foundation of China[91857110] ; National Natural Science Foundation of China[81670740] ; National Natural Science Foundation of China[82200885] ; National Natural Science Fund for Excellent Young Scholars of China[81722012] ; Zhejiang Provincial Natural Science Foundation of China[LZ21H070001] ; Innovative Institute of Basic Medical Sciences of Zhejiang University ; Construction Fund of Medical Key Disciplines of Hangzhou ; National Science and Technology Major Project[2018ZX09711002- 004/018] ; National Key R&D Program of China[2018YFA0800403] ; China Postdoctoral Science Foundation[2021 M703349] ; Shanghai Science and Technology Development Funds[22YF1456900] ; Innovative Research Team of High - Level Local Universities in Shanghai[SSMU- ZDCX20181202] ; Innovative Research Team of High - Level Local Universities in Shanghai[SHSMU- ZDCX20212700] ; Shanghai Municipal Science and Technology Committee of Shanghai outstanding academic leaders plan[22XD1400600] |
| WOS研究方向 | Cell Biology ; Research & Experimental Medicine |
| 语种 | 英语 |
| 出版者 | AMER ASSOC ADVANCEMENT SCIENCE |
| WOS记录号 | WOS:001158469100006 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309213]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wu, Linshi; Meng, Zhuoxian; Tan, Minjia; Li, Jingya |
| 作者单位 | 1.Zhejiang Univ, Affiliated Hosp 2, Dept Pathol & Pathophysiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shanghai Jiao Tong Univ, Renji Hosp, Dept Endocrinol & Metab, Sch Med, Shanghai 200127, Peoples R China 4.Zhejiang Univ, Sch Med, Dept Pathol, Key Lab Dis Prote Zhejiang Prov, Hangzhou 310058, Zhejiang, Peoples R China 5.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China 7.Zhejiang Univ, Dept Cardiol, Sch Med, Affiliated Hosp 2, Zhangzhou 310058, Zhejiang, Peoples R China 8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lu, Yuting,Xu, Junyu,Li, Yufeng,et al. DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition[J]. SCIENCE TRANSLATIONAL MEDICINE,2024,16(733):16. |
| APA | Lu, Yuting.,Xu, Junyu.,Li, Yufeng.,Wang, Ruoran.,Dai, Chengqiu.,...&Li, Jingya.(2024).DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition.SCIENCE TRANSLATIONAL MEDICINE,16(733),16. |
| MLA | Lu, Yuting,et al."DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition".SCIENCE TRANSLATIONAL MEDICINE 16.733(2024):16. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。