Identification of oleoylethanolamide as an endogenous ligand for HIF-3 alpha
文献类型：期刊论文
| 作者 | Diao, Xiaotong7; Ye, Fei5,6; Zhang, Meina7; Ren, Xintong7; Tian, Xiaoxu4; Lu, Jingping3; Sun, Xiangnan7; Hou, Zeng1,2; Chen, Xiaoyu7; Li, Fengwei7 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2022-05-09 |
| 卷号 | 13期号:1页码:12 |
| DOI | 10.1038/s41467-022-30338-z |
| 通讯作者 | Rastinejad, Fraydoon(fraydoon.rastinejad@ndm.ox.ac.uk) ; Luo, Cheng(cluo@simm.ac.cn) ; Wu, Dalei(dlwu@sdu.edu.cn) |
| 英文摘要 | Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3 alpha ligand and further revealed its mechanism of action. Hypoxia-inducible factors (HIFs) are alpha/beta heterodimeric transcription factors modulating cellular responses to the low oxygen condition. Among three HIF-alpha isoforms, HIF-3 alpha is the least studied to date. Here we show that oleoylethanolamide (OEA), a physiological lipid known to regulate food intake and metabolism, binds selectively to HIF-3 alpha. Through crystallographic analysis of HIF-3 alpha/beta heterodimer in both apo and OEA-bound forms, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics (MD) simulations, and biochemical and cell-based assays, we unveil the molecular mechanism of OEA entry and binding to the PAS-B pocket of HIF-3 alpha, and show that it leads to enhanced heterodimer stability and functional modulation of HIF-3. The identification of HIF-3 alpha as a selective lipid sensor is consistent with recent human genetic findings linking HIF-3 alpha with obesity, and demonstrates that endogenous metabolites can directly interact with HIF-alpha proteins to modulate their activities, potentially as a regulatory mechanism supplementary to the well-known oxygen-dependent HIF-alpha hydroxylation. |
| WOS关键词 | HYPOXIA-INDUCIBLE FACTOR-3 ; TRANSCRIPTION FACTOR ; NEGATIVE REGULATOR ; HIF-ALPHA ; PROTEIN ; DOMAIN ; ACTIVATION ; HYDROXYLATION ; INTEGRATION ; EXPRESSION |
| 资助项目 | State Key laboratory of Microbial Technology of Shandong University ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; Shandong Provincial Natural Science Foundation, China[ZR2021JQ30] ; National Key R&D Program of China[2021ZD0203900] ; Taishan Scholars Program of Shandong Province[tsqn201909004] ; State Key Laboratory of Drug Research[SIMM2105KF-03] ; Science and Technology Commission of Shanghai Municipality[18DZ2210200] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine ; National Institutes of Health[R01DK118297] ; Construction and Operation of Zhangjiang Laboratory (II)[19DZ2260100] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000792848500009 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300992]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Rastinejad, Fraydoon; Luo, Cheng; Wu, Dalei |
| 作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310053, Peoples R China 3.Univ Oxford, Target Discovery Inst, NDM Res Bldg,Old Rd Campus, Oxford OX3 7FZ, England 4.Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China 5.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China 6.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 310053, Peoples R China 7.Shandong Univ, Helmholtz Int Lab, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Diao, Xiaotong,Ye, Fei,Zhang, Meina,et al. Identification of oleoylethanolamide as an endogenous ligand for HIF-3 alpha[J]. NATURE COMMUNICATIONS,2022,13(1):12. |
| APA | Diao, Xiaotong.,Ye, Fei.,Zhang, Meina.,Ren, Xintong.,Tian, Xiaoxu.,...&Wu, Dalei.(2022).Identification of oleoylethanolamide as an endogenous ligand for HIF-3 alpha.NATURE COMMUNICATIONS,13(1),12. |
| MLA | Diao, Xiaotong,et al."Identification of oleoylethanolamide as an endogenous ligand for HIF-3 alpha".NATURE COMMUNICATIONS 13.1(2022):12. |
入库方式： OAI收割
来源：上海药物研究所
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