Cathepsin B is a mediator of organelle-specific initiation of ferroptosis

Feimei Kuang, Jiao Liu, Changfeng Li, Rui Kang, Daolin Tang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Ferroptosis is a type of non-apoptotic regulated cell death that involves excessive iron accumulation and subsequent lipid peroxidation. Although the antioxidant mechanisms of ferroptosis have been extensively studied recently, little is known about the interactions between the different organelles that control ferroptosis. Here, we show that the translocation of lysosomal cysteine protease cathepsin B (CTSB) into the nucleus is an important molecular event that mediates organelle-specific initiation of ferroptosis in human pancreatic cancer cells. Iron-dependent lysosomal membrane permeability triggers the release of CTSB from the lysosome to nucleus during ferroptosis. Mechanistically, nuclear CTSB accumulation causes DNA damage and subsequent activation of the stimulator of interferon response CGAMP interactor 1 (STING1/STING)-dependent DNA sensor pathway, which ultimately leads to autophagy-dependent ferroptosis. Consequently, the genetic inhibition of CTSB-dependent STING1 activation by RNAi prevents ferroptosis in cell culture and animal models. These new findings not only enhance our understanding of the mechanism by which organelles specifically trigger ferroptosis, but also may provide a potential way to enhance the anticancer activity of ferroptosis therapy.

Original languageEnglish (US)
Pages (from-to)1464-1469
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume533
Issue number4
DOIs
StatePublished - Dec 17 2020

Keywords

  • Autophagy
  • Cathepsin B
  • DNA damage
  • Ferroptosis
  • Lysosome
  • STING1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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