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

Autor: Kuang F; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China., Liu J; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China., Li C; Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China., Kang R; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: rui.kang@utsouthwestern.edu., Tang D; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510510, China; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2020 Dec 17; Vol. 533 (4), pp. 1464-1469. Date of Electronic Publication: 2020 Oct 22.
DOI: 10.1016/j.bbrc.2020.10.035
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest or financial interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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