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The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI

Ismael Sánchez-Vera1, Sonia Núñez-Vázquez1, José Saura-Esteller1

  • 1Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Oncobell-IDIBELL (Institut d'Investigació Biomèdica de Bellvitge), 08907 L'Hospitalet de Llobregat, Spain.

International Journal of Molecular Sciences
|May 13, 2023
PubMed

Insights

Fluorizoline triggers apoptosis by targeting prohibitins and activating the integrated stress response (ISR). The mitochondrial-stress-related eIF2α kinase HRI mediates this ISR activation, despite other kinases showing compensatory functions.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of apoptosis
  • Stress response pathways

Background:

  • Fluorizoline induces apoptosis by targeting prohibitins (PHBs) and upregulating the BH3-only protein NOXA.
  • This process is transcriptionally controlled by integrated stress response (ISR)-related transcription factors ATF3 and ATF4.

Purpose of the Study:

  • To identify the specific eIF2α kinase responsible for ISR activation induced by fluorizoline.
  • To investigate the compensatory roles of eIF2α kinases in fluorizoline-induced apoptosis.

Main Methods:

  • Utilized an ISR inhibitor (ISRIB) and simultaneous downregulation of all four eIF2α kinases.
  • Assessed endoplasmic reticulum (ER) stress via PERK activation.
  • Investigated the role of HRI in mediating ISR activation.

Main Results:

  • Both ISR inhibition and downregulation of all eIF2α kinases conferred resistance to fluorizoline-induced apoptosis.
  • Fluorizoline treatment induced ER stress and PERK activation, but PERK was not directly involved in ISR activation.
  • eIF2α kinases demonstrated functional compensation.
  • The mitochondrial-stress-related eIF2α kinase HRI was identified as the mediator of ISR activation.

Conclusions:

  • HRI is the primary eIF2α kinase mediating ISR activation in response to fluorizoline.
  • The compensatory mechanisms among eIF2α kinases influence cellular response to fluorizoline.
  • Understanding this pathway offers insights into targeted apoptosis induction.
Keywords:
ER-stressHRIISRapoptosisfluorizolinemitochondrial-stressprohibitin

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