ER-tethered RNA-binding protein controls NADPH oxidase translation for hydrogen peroxide homeostasis

作者全名：Pei, Xintong; Wang, Zhe; He, Wenting; Li, Shunqin; Chen, Xiaowei; Fan, Zhen; Lan, Yongguang; Yuan, Lin; Xu, Pingyong

作者地址：[Pei, Xintong; Wang, Zhe; He, Wenting; Li, Shunqin; Lan, Yongguang; Yuan, Lin; Xu, Pingyong] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Key Lab Biomacromol CAS, Beijing 100101, Peoples R China; [Pei, Xintong; Wang, Zhe; Li, Shunqin; Xu, Pingyong] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100101, Peoples R China; [Chen, Xiaowei; Fan, Zhen] Chinese Acad Sci, Ctr High Throughput Sequencing, Inst Biophys, Core Facil Prot Res, Beijing 100101, Peoples R China; [Xu, Pingyong] Chongqing Med Univ, Dept Clin Lab, Childrens Hosp, Chongqing 400014, Peoples R China

通信作者：Yuan, L; Xu, PY (通讯作者)，Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Key Lab Biomacromol CAS, Beijing 100101, Peoples R China.

来源：REDOX BIOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001214567800001

JCR分区：Q1

影响因子：10.7

年份：2024

卷号：71

期号：　

开始页：　

结束页：　

文献类型：Article

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摘要：Hydrogen peroxide (H 2 O 2 ) functions as a signaling molecule in diverse cellular processes. While cells have evolved the capability to detect and manage changes in H 2 O 2 levels, the mechanisms regulating key H 2 O 2 -producing enzymes to maintain optimal levels, especially in pancreatic beta cells with notably weak antioxidative defense, remain unclear. We found that the protein EI24 responds to changes in H 2 O 2 concentration and regulates the production of H 2 O 2 by controlling the translation of NOX4, an enzyme that is constitutively active, achieved by recruiting an RNA-binding protein, RTRAF, to the 3 ' -UTR of Nox4 . Depleting EI24 results in RTRAF relocating into the nucleus, releasing the brake on NOX4 translation. The excessive production of H 2 O 2 by liberated NOX4 further suppresses the translation of the key transcription factor MafA , ultimately preventing its binding to the Ins2 gene promoter and subsequent transcription of insulin. Treatment with a specific NOX4 inhibitor or the antioxidant NAC reversed these effects and alleviated the diabetic symptoms in beta-cell specific Ei24 -KO mice. This study revealed a new mechanism through which cells regulate oxidative stress at the translational level, involving an ER-tethered RNA-binding protein that controls the expression of the key H 2 O 2 -producing enzyme NOX4.

基金机构：National Key R & D Program of China [2022YFC3400600-2, 2022ZD0211900]; National Natural Science Foundation of China [92254306, 21927813, 32227802, 31970704, T2394513]; Strategic Priority Research Program of Chinese Academy of Sciences [XDB37040301]

基金资助正文：This project was supported by the National Key R & D Program of China (2022YFC3400600-2 and 2022ZD0211900), the National Natural Science Foundation of China (92254306, 21927813, 32227802, 31970704 and T2394513), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB37040301). We thank Dr. Hong Zhang (Institute of Biophysics, Chinese Academy of Sciences) and Dr. Weiping Zhang (Department of Pathophysiology, Second Military Medical University) for the mice of Ei24 flox/flox and Ins2-Cre, respectively. We thank Dr. Lei Wang (Institute of Biophysics, Chinese Academy of Sciences) for plasmid pHyPer-ER, Dr. Xianen Zhang (Institute of Biophysics, Chinese Academy of Sciences) for plamid pLVX-HyPer, Dr. Chang Chen (Institute of Biophysics, Chinese Academy of Sciences) for plasmids pcDNA3.1-Grx1-roGFP2cyto and pcDNA3.1-rosfGFPiEER, and Dr. Xiaorong Zhang (Institute of Biophysics, Chinese Academy of Sciences) for plasmid psiCHECK2. We thank Dr. Rong Ye and Dr. Jiajia Wang (Institute of Biophysics, Chinese Academy of Sciences) for their discussions regarding the methodology of mRNA sequencing and data analysis. We thank Prof. Haiteng Deng and Dr. Chongchong Zhao in Proteinomics Facility at Technology Center for Protein Sciences, Tsinghua University, for protein MS analysis. We thank Dr. Hong Zhang, Dr. Chen Chang and Dr. Xiaorong Zhang for their insightful discussion.