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Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis

Xin Chen1,2,3, Xinxin Song3, Jingbo Li3

  • 1DAMP Lab, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.

Autophagy
|April 11, 2022
PubMed

Insights

Researchers identified hippocalcin like 1 (HPCAL1) as a novel autophagy receptor that promotes ferroptosis by degrading cadherin 2 (CDH2). Inhibiting HPCAL1 blocks ferroptosis, offering potential therapeutic targets for diseases like cancer and pancreatitis.

Area of Science:

  • Molecular Biology
  • Cell Death Mechanisms
  • Autophagy Research

Background:

  • Selective autophagy maintains cellular homeostasis but its role in cell death is not fully understood.
  • Ferroptosis is a regulated form of cell death implicated in various pathologies.
  • Understanding the molecular players in ferroptosis is crucial for therapeutic development.

Purpose of the Study:

  • To identify novel autophagy receptors involved in ferroptosis.
  • To elucidate the mechanism by which selective autophagy regulates ferroptosis.
  • To explore therapeutic strategies targeting ferroptosis.

Main Methods:

  • Quantitative proteomic analysis to identify autophagy receptors.
  • Site-directed mutagenesis and bioinformatic analysis to understand protein interactions.
  • Small molecule drug screening for ferroptosis inhibitors.
  • In vivo studies using mouse models for tumor suppression and pancreatitis.

Main Results:

  • Hippocalcin like 1 (HPCAL1) was identified as a novel autophagy receptor for cadherin 2 (CDH2) degradation during ferroptosis.
  • HPCAL1-dependent CDH2 depletion promotes ferroptosis by reducing membrane tension and increasing lipid peroxidation.
  • Phosphorylation of HPCAL1 by protein kinase C theta (PRKCQ) and a specific LC3-interacting region (LIR) motif are essential for CDH2 degradation.
  • A novel ferroptosis inhibitor targeting HPCAL1 expression was identified.
  • Inhibition of HPCAL1, genetically or pharmacologically, prevented ferroptosis-induced tumor suppression and pancreatitis in mouse models.

Conclusions:

  • Selective autophagy, mediated by HPCAL1, plays a critical role in promoting ferroptotic cell death.
  • The HPCAL1-CDH2 axis represents a novel regulatory pathway in ferroptosis.
  • Targeting HPCAL1 offers a potential therapeutic strategy for diseases involving ferroptosis.
Keywords:
Autophagydegradationferroptosisinhibitormechanotransductionpancreasphosphorylation

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