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

作者：Yunqi Jiang, Yuhui Qiao, Dan He, Aiju Tian, Zijian Li · 发表于：Cell Death and Differentiation · 年份：2023 · DOI：10.1038/s41418-022-01110-z · 被引用次数：46 · 研究领域：Ferroptosis and cancer prognosis、RNA modifications and cancer、Ubiquitin and proteasome pathways

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, pro...