SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier
文献类型： 外文期刊
作者： Feng, Runyang 1 ; Fang, Zheyan 1 ; Zhao, Shuang 2 ; Zhang, You-en 3 ; Wu, Na 4 ; Guo, Zhenyang 1 ; Zhong, Xin 1 ; Jiang, Bixuan 5 ; Xu, Hongfei 7 ; Hong, Hangnan 1 ; Zhang, Zhentao 1 ; Abdurahman, Mukaddas 1 ; Yu, Xueting 1 ; Geng, Jilong 1 ; Nie, Xiansu 1 ; Abuduwahapi, Supuya 1 ; Huang, Dong 1 ; Zhao, Gang 1 ; Zhang, Wenbin 8 ; Lu, Hao 1 ; Shen, Li 1 ; Zhao, Xin 1 ; Chen, Zhaoyang 9 ; Guo, Junjie 10 ; Zheng, Hongchao 4 ; He, Yue 11 ; Wu, Sanwu 3 ; Peng, Jiayin 12 ; Song, Jiawen 12 ; Wang, Xiao 13 ; Li, Haomin 15 ; Huang, Yuli 16 ; Qin, Shengying 5 ; Lu, Haojie 17 ; Wang, Xiangdong 19 ; Zhao, Jianguo 14 ; Huang, Lei 22 ; Zhao, Yun 12 ; Li, Peng 1 ; Ge, Junbo 1 ; Li, Hua 1 ;
作者机构： 1.Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai 200032, Peoples R China
2.Shanghai Xuhui Dist Cent Hosp, Dept Med Examinat, Shanghai 200031, Peoples R China
3.Hubei Univ Med, Renmin Hosp, Dept Cardiol, Arteriosclerosis Cardiovasc Dis Clin Med Res Ctr H, Shiyan 442000, Hubei, Peoples R China
4.Shanghai Xuhui Dist Cent Hosp, Dept Cardiol, Shanghai 200031, Peoples R China
5.Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China
6.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China
7.Soochow Univ, Dept Forens Med, Suzhou 215000, Peoples R China
8.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Cardiol, Sch Med, Hangzhou 310020, Peoples R China
9.Fujian Med Univ Union Hosp, Heart Ctr Fujian Prov, Dept Cardiol, Fuzhou 350001, Peoples R China
10.Qingdao Univ, Dept Cardiol, Affiliated Hosp, Qingdao 266003, Peoples R China
11.Shanghai Eighth Peoples Hosp, Dept Cardiol, Shanghai, Peoples R China
12.Univ Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol,Chinese Acad Sci, Shanghai 200031, Peoples R China
13.Chinese Acad Agr Sci, State Key Lab Anim Nutr, Inst Anim Sci, Beijing 100193, Peoples R China
14.Chinese Acad Sci, State Key Lab Stem Cell & Reprod Biol, Inst Zool, Beijing 100101, Peoples R China
15.Zhejiang Univ, Childrens Hosp, Clin Data Ctr, Natl Clin Res Ctr Child Hlth,Sch Med, Hangzhou 310052, Zhejiang, Peoples R China
16.Southern Med Univ, Shunde Hosp, Dept Cardiol, Guangzhou 528399, Guangdong, Peoples R China
17.Fudan Univ, Dept Chem, Shanghai 200032, Peoples R China
18.Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China
19.Fudan Univ, Zhongshan Hosp, Shanghai Med Coll, Dept Pulm & Crit Care Med, Shanghai 200032, Peoples R China
20.Univ Chinese Acad Sci, Savaid Med Sch, Beijing 100049, Peoples R China
21.Beijing Inst Stem Cell & Regenerat Med, Beijing 100101, Peoples R China
22.Univ Massachusetts, Chan Med Sch, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA
23.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
24.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China
25.Natl Basic Sci Ctr Complex Syst Panvascular Interv, Shanghai 200032, Peoples R China
26.Natl Clin Res Ctr Intervent Med, Shanghai 200032, Peoples R China
27.Shanghai Clin Res Ctr Intervent Med, Shanghai 200032, Peoples R China
28.Natl Hlth Commiss, Key Lab Viral Heart Dis, Shanghai 200032, Peoples R China
29.Chinese Acad Med Sci, Key Lab Viral Heart Dis, Shanghai 200032, Peoples R China
关键词： ATF2; endothelial barrier function; epigenetic regulation; myristoylation; nucleoplasmic translocation; SIRT6
期刊名称：ADVANCED SCIENCE （ 影响因子：14.1； 五年影响因子：15.6 ）
ISSN：
年卷期： 2025 年
页码：
收录情况： SCI
摘要： Cardiovascular diseases (CVDs) progression is significantly modulated by epigenetic mechanisms, particularly through Sirtuin 6 (SIRT6), a key NAD(+)-dependent deacetylase in the sirtuin family. Though essential for cardiovascular homeostasis, the effects of SIRT6-mediated lysine myristoylation on CVDs progression remain largely unexplored due to detection limitations. This study developes an innovative lysine-myristoylated peptide enrichment technique, identifying mutant SIRT6 (H133Y) with high myristoyl affinity but deficient demyristoylase activity. This advancement enables identification of 15 previously unrecognized human lysine-myristoylated proteins. Further study demonstrates that SIRT6 demyristoylates activating transcription factor 2 (ATF2) at K296 and regulates its nucleoplasmic translocation. Through 4D label-free mass spectrometry and molecular approaches, it is revealed that decreased nuclear localization of ATF2 results in reduced Protein kinase C delta type (PRKCD) expression, establishing a SIRT6/Myr-ATF2/PRKCD/VE-Cadherin pathway that enhances endothelial barrier integrity under high myristate conditions. These findings are validated in vitro (gene overexpression/knockdown cells) and in vivo (SIRT6 knockout/double-transgenic mice). The study provides both a novel method for identifying lysine-myristoylated proteins and critical insights into SIRT6 demyristoylation biology. Modulating the SIRT6 pathway might yield therapies to strengthen endothelial integrity and mitigate vascular dysfunction in CVDs, offering promising clinical translation avenues.
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