Int J Biol Sci 2023; 19(5):1369-1381. doi:10.7150/ijbs.80800 This issue Cite

Research Paper

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Hang Zhu1,2*, Zhe Dai1*, Xiaoman Liu1*, Hao Zhou1, Yijin Wang1✉

1. School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
2. Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.
* These authors contributed equally to this article.

Citation:
Zhu H, Dai Z, Liu X, Zhou H, Wang Y. Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation. Int J Biol Sci 2023; 19(5):1369-1381. doi:10.7150/ijbs.80800. https://www.ijbs.com/v19p1369.htm
Other styles

File import instruction

Abstract

Graphic abstract

Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3-/-) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

Keywords: STK3, KEAP1, Nrf2, mitochondria, septic cardiomyopathy.


Citation styles

APA
Zhu, H., Dai, Z., Liu, X., Zhou, H., Wang, Y. (2023). Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation. International Journal of Biological Sciences, 19(5), 1369-1381. https://doi.org/10.7150/ijbs.80800.

ACS
Zhu, H.; Dai, Z.; Liu, X.; Zhou, H.; Wang, Y. Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation. Int. J. Biol. Sci. 2023, 19 (5), 1369-1381. DOI: 10.7150/ijbs.80800.

NLM
Zhu H, Dai Z, Liu X, Zhou H, Wang Y. Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation. Int J Biol Sci 2023; 19(5):1369-1381. doi:10.7150/ijbs.80800. https://www.ijbs.com/v19p1369.htm

CSE
Zhu H, Dai Z, Liu X, Zhou H, Wang Y. 2023. Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation. Int J Biol Sci. 19(5):1369-1381.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image