Septin4 promotes cardiomyocytes apoptosis by enhancing the VHL-mediated degradation of HIF-1\u03b1

Shaojun Wu,Shilong You,Ying Zhang,Naijin Zhang,Saien Lu,Yingxian Sun

doi:10.1038/s41420-021-00563-4

Abstract

Septin4, a protein localized at mitochondrion, can promote cells apoptosis mainly by binding XIAP (X-linked inhibitors of apoptosis), however, nothing is known about the role and mechanism of Septin4 in cardiomyocytes apoptosis. Here in the current study, we report that HIF-1α (hypoxia-inducible factor 1 alpha) is a novel interacting protein with Septin4 at Septin4-GTPase domain. In addition, Septin4 enhances the binding between HIF-1α and the E3 ubiquitin ligase VHL (von Hippel-Lindau protein) to down-regulate HIF-1α, and by reducing cardio-protective factor HIF-1α levels, Septin4 aggravated the hypoxia-induced cardiomyocytes apoptosis. We believe these findings will be beneficial to provide effective strategies for clinical treatment of myocardial ischemia and the subsequent injury caused by myocardial hypoxia.

Highlights

Myocardial ischemia can lead to insufficient oxygen supply to the myocardium, which is called myocardial hypoxia; myocardial hypoxia can result in cardiomyocytes apoptosis and necrosis [1], which can further develop into myocardial infarction and endanger the life of the patient
HIF-1α could hardly be detected in cells, which is due to the existence of VHL, a recognizing subunit of an E3 ubiquitin ligase complex that mediates the degradation of HIF-1α through the UPS [4,5,6]
The current study found the similar mechanism for the first time in cardiomyocytes that Septin4 can enhance the binding between HIF-1α and the E3 ubiquitin ligase VHL, and Septin4 reduces the expression levels of the cardio-protective factor HIF-1α through UPS pathway

Summary

Introduction

Myocardial ischemia can lead to insufficient oxygen supply to the myocardium, which is called myocardial hypoxia; myocardial hypoxia can result in cardiomyocytes apoptosis and necrosis [1], which can further develop into myocardial infarction and endanger the life of the patient. We found that the cardio-protective factor HIF-1α is a novel interacting protein with Septin4 via Septin4GTPase domain in hypoxia-induced cardiomyocytes apoptosis.

Results

Conclusion