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14-3-3/HIP-55 complex attenuates cardiomyocyte apoptosis

Yunqi Jiang1, Dannya Estau2, Yuhui Qiao1

  • 1Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China; Beijing Key Laboratory of Cardiovascular Receptors Research, State Key Laboratory of Vascular Homeostasis and Remodeling, and NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China.

Journal of Molecular and Cellular Cardiology
|July 17, 2025
PubMed

Insights

The 14-3-3/HIP-55 protein complex protects heart cells from death after myocardial infarction (MI). This complex formation, regulated by RSK1 phosphorylation, suppresses the ASK1 apoptotic pathway, offering a potential therapeutic target for heart damage.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Death Research

Background:

  • Myocardial infarction (MI) is a major cause of global mortality, primarily due to cardiomyocyte death.
  • Early endogenous cardioprotection is critical for limiting infarct size and improving patient outcomes.
  • 14-3-3 proteins are known to be involved in cardiomyocyte survival, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which 14-3-3 proteins protect cardiomyocytes against MI-induced death.
  • To identify the role of HIP-55 protein in 14-3-3 mediated cardioprotection.
  • To investigate the signaling pathway involving RSK1, 14-3-3, and HIP-55 in response to cardiac injury.

Main Methods:

  • Investigated the interaction between 14-3-3 and HIP-55 in cardiomyocytes subjected to MI injury.
  • Utilized in vitro and in vivo models of myocardial infarction.
  • Employed RSK1 kinase assays and site-directed mutagenesis (S269A/T291A) of HIP-55 to study phosphorylation-dependent complex formation and its functional consequences.
  • Assessed cardiomyocyte apoptosis and the ASK1 apoptotic pathway.

Main Results:

  • Identified a novel complex formed between 14-3-3 and HIP-55 that suppresses MI-induced cardiomyocyte death.
  • Demonstrated that HIP-55 confers protection against MI-induced cardiomyocyte apoptosis.
  • Showed that RSK1 phosphorylates HIP-55 at S269/T291 sites, promoting 14-3-3/HIP-55 complex formation and inhibiting the ASK1 apoptotic pathway.
  • Mutated HIP-55 (S269A/T291A), unable to form the complex, lost its protective effect against MI-induced apoptosis.

Conclusions:

  • The 14-3-3/HIP-55 complex is a key mediator of cardiomyocyte survival following myocardial infarction.
  • RSK1-mediated phosphorylation of HIP-55 is essential for the formation of this protective complex.
  • Targeting the 14-3-3/HIP-55 interaction presents a promising therapeutic strategy for mitigating cardiac damage in acute myocardial injury.

Keywords:
14-3-3Cell deathHIP-55Myocardial infarction

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