1. Academic Validation
  2. Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction

Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction

  • Cell Death Differ. 2023 Jan 13. doi: 10.1038/s41418-022-01110-z.
Yunqi Jiang # 1 Yuhui Qiao # 1 Dan He 1 Aiju Tian 1 Zijian Li 2 3
Affiliations

Affiliations

  • 1 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Beijing Key Laboratory of Cardiovascular Receptors Research; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China.
  • 2 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Beijing Key Laboratory of Cardiovascular Receptors Research; Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China. lizijian@bjmu.edu.cn.
  • 3 Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China. lizijian@bjmu.edu.cn.
  • # Contributed equally.
Abstract

Ischemic heart disease is a leading cause of death worldwide. Myocardial infarction (MI) results in cardiac damage due to cell death and insufficient cardiomyocyte self-renewal. Ferroptosis, a novel type of cell death, has recently been shown as a key cause of cardiomyocyte death after MI. However, the complicated regulation mechanisms involved in Ferroptosis, especially how Ferroptosis is integrated into classical cell survival/death pathways, are still unclear. Here, we discovered that HIP-55, a novel adaptor protein, acts as a hub protein for the integration of the Ferroptosis mechanism into the classical Akt cell survival and MAP4K1 cell death pathways for MI injury. The expression of HIP-55 is induced in MI. Genetic deletion of HIP-55 increased cardiomyocyte Ferroptosis and MI injury, whereas cardiac-specific overexpression of HIP-55 significantly alleviated cardiomyocyte Ferroptosis and MI injury. Mechanistically, HIP-55 was identified as a new Akt substrate. Akt phosphorylates HIP-55 at S269/T291 sites and further HIP-55 directs Akt signaling to negatively regulate the MAP4K1 pathway against MI injury in a site-specific manner. S269A/T291A-mutated HIP-55 (HIP-55AA), which is defective in Akt phosphorylation and significantly decreases the interaction between HIP-55 and MAP4K1, failed to inhibit the MAP4K1/GPX4 Ferroptosis pathway. In line with this mechanism, cardiac-specific overexpression of HIP-55WT mice, but not cardiac-specific overexpression of HIP-55AA mice, protected cardiomyocytes against MI-induced Ferroptosis and cardiac injury in vivo. These findings suggest that HIP-55 rewired the classical Akt (cell survival) and MAPK (cell death) pathways into Ferroptosis mechanism in MI injury. HIP-55 may be a new therapeutic target for myocardial damage.

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