An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage
Naijin Zhang,
Ying Zhang,
Wei Miao,
Chuning Shi,
Zihan Chen,
Boquan Wu,
Yuanming Zou,
Qiushi Ma,
Shilong You,
Saien Lu,
Xinyue Huang,
Jingwei Liu,
Jiaqi Xu,
Liu Cao,
Yingxian Sun
Affiliations
Naijin Zhang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China
Ying Zhang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China
Wei Miao
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Chuning Shi
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Zihan Chen
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Boquan Wu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Yuanming Zou
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Qiushi Ma
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Shilong You
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Saien Lu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Xinyue Huang
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Jingwei Liu
Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China
Jiaqi Xu
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China
Liu Cao
Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of School of Basic Medicine, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Corresponding author. Key Laboratory of Medical Cell Biology, Ministry of Education, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China.
Yingxian Sun
Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China; Institute of Health Sciences, China Medical University, 77 Puhe Road, Shenbei New District, Shenyang, 110001, Liaoning Province, People's Republic of China; Corresponding author. Department of Cardiology, First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
Oxidative stress-associated endothelial damage is the initiation factor of cardiovascular disease, and protein posttranslational modifications play critical roles in this process. Bcl-2-associated athanogene 3 (BAG3) is a molecular chaperone regulator of the BAG family, which interacts with various proteins and influences cell survival by activating multiple pathways. BAG3 undergoes posttranslational modifications; however, research evaluating BAG3 acetylation and its regulatory mechanism is lacking. In addition, the interacting protein and regulatory mechanism of BAG3 in oxidative stress-associated endothelial damage remain unclear. Here, key molecular interactions and protein modifications of BAG3 were identified in oxidative stress-associated endothelial damage. Endothelial-specific BAG3 knockout in the mouse model starkly enhances oxidative stress-associated endothelial damage and vascular remodeling, while BAG3 overexpression in mice significantly relieves this process. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1), causing oxidative stress, was identified as a novel physiological substrate of BAG3. Indeed, BAG3 binds to PARP1's BRCT domain to promote its ubiquitination (K249 residue) by enhancing the E3 ubiquitin ligase WWP2, which leads to proteasome-induced PARP1 degradation. Furthermore, we surprisingly found that BAG3 represents a new substrate of the acetyltransferase CREB-binding protein (CBP) and the deacetylase Sirtuin 2 (SIRT2) under physiological conditions. CBP/SIRT2 interacted with BAG3 and acetylated/deacetylated BAG3's K431 residue. Finally, deacetylated BAG3 promoted the ubiquitination of PARP1. This work reveals a novel regulatory system, with deacetylation-dependent regulation of BAG3 promoting PARP1 ubiquitination and degradation via enhancing WWP2, which is one possible mechanism to decrease vulnerability of oxidative stress in endothelial cells.
