SIRT6 Lysine‐Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE‐Cadherin Pathway Regulating Vascular Endothelial Barrier

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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Publication Details

Journal
Advanced Science
Published
2025-08-14
DOI
https://doi.org/10.1002/advs.202504948
Primary Topic
Neurological Disorders and Treatments
Type
article
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article

SIRT6 Lysine‐Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE‐Cadherin Pathway Regulating Vascular Endothelial Barrier

Hua Li, Hongchao Zheng, Xin Nie, Jiawen Song et al.
Advanced Science
Neurological Disorders and Treatments
article

SIRT6 Lysine‐Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE‐Cadherin Pathway Regulating Vascular Endothelial Barrier

Hua Li, Hongchao Zheng, Xin Nie, Jiawen Song, Junjie Guo, Shengying Qin, Xin Zhao, Youen Zhang, San-wu Wu, Jianguo Zhao, Bixuan Jiang, Zheyan Fang, Hongfei Xu, Zhenyang Guo, Yue He, Ji Geng, Hao Lu, Haomin Li, Runyang Feng, Shen Li, Xiangdong Wang, Peng Li, Xiao Wang, Na Wu, Zhentao Zhang, Zhaoyang Chen, Jiayin Peng, Wenbin Zhang, Haojie Lu, Lei Huang, Gang Zhao, Shuang Zhao, Dong Huang, Xueting Yu, Xin Zhong, Junbo Ge, Mukaddas Abdurahman, Hangnan Hong, Yun Zhao, Supuya Abuduwahapi
article en

Abstract

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.

Advanced ScienceVol. 12(41)
Qingdao University (CN), Hubei University of Medicine (CN), Fujian Medical University (CN), Shanghai Medical College of Fudan University (CN), National Institute for Basic Biology (JP), University of Massachusetts Chan Medical School (US), Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Fudan University (CN), National Health and Family Planning Commission (CN), Sir Run Run Shaw Hospital (CN), ShanghaiTech University (CN), Soochow University (CN), National Clinical Research Center for Digestive Diseases (CN), The First People's Hospital of Shunde (CN), National Center for PTSD (US), Children's Hospital of Zhejiang University (CN), Affiliated Hospital of Qingdao University (CN), Shanghai Xuhui Central Hospital (CN), Center for Excellence in Molecular Cell Science (CN), Zhongshan Hospital (CN), Shanghai Eighth People Hospital (CN), Chinese Academy of Agricultural Sciences (CN), China Academy of Chinese Medical Sciences (CN), Union Hospital (US), Shanghai Clinical Research Center (CN), Union Hospital (CN), University of Chinese Academy of Sciences (CN), Institute of Zoology (CN), Southern Medical University (CN)
Openalex Percentile: Top 74%
Neurological Disorders and Treatments
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