Copper-dependent autophagic degradation of GPX4 drives ferroptosis

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly un...

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Autores principales: Xue, Qian, Yan, Ding, Chen, Xi, Li, Xiaofen, Kang, Rui, Klionsky, Daniel J., Kroemer, Guido, Chen, Xin, Tang, Daolin, Liu, Jinbao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10283421/
https://www.ncbi.nlm.nih.gov/pubmed/36622894
http://dx.doi.org/10.1080/15548627.2023.2165323
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author Xue, Qian
Yan, Ding
Chen, Xi
Li, Xiaofen
Kang, Rui
Klionsky, Daniel J.
Kroemer, Guido
Chen, Xin
Tang, Daolin
Liu, Jinbao
author_facet Xue, Qian
Yan, Ding
Chen, Xi
Li, Xiaofen
Kang, Rui
Klionsky, Daniel J.
Kroemer, Guido
Chen, Xin
Tang, Daolin
Liu, Jinbao
author_sort Xue, Qian
collection PubMed
description Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly understood. Here, we report an unexpected role for copper in promoting ferroptotic cell death, but not cuproptosis, by inducing macroautophagic/autophagic degradation of GPX4. Copper chelators reduce ferroptosis sensitivity but do not inhibit other types of cell death, such as apoptosis, necroptosis, and alkaliptosis. Conversely, exogenous copper increases GPX4 ubiquitination and the formation of GPX4 aggregates by directly binding to GPX4 protein cysteines C107 and C148. TAX1BP1 (Tax1 binding protein 1) then acts as an autophagic receptor for GPX4 degradation and subsequent ferroptosis in response to copper stress. Consequently, copper enhances ferroptosis-mediated tumor suppression in a mouse model of pancreatic cancer tumor, whereas copper chelators attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into the link between metal stress and autophagy-dependent cell death. Abbreviations: CALCOCO2, calcium binding and coiled-coil domain 2; GPX4, glutathione peroxidase 4; MAP1LC3A/B, microtubule associated protein 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear receptor coactivator 4; OPTN, optineurin; PDAC, pancreatic ductal adenocarcinoma; RIPK1, receptor interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member 1; SQSTM1, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.
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spelling pubmed-102834212023-06-22 Copper-dependent autophagic degradation of GPX4 drives ferroptosis Xue, Qian Yan, Ding Chen, Xi Li, Xiaofen Kang, Rui Klionsky, Daniel J. Kroemer, Guido Chen, Xin Tang, Daolin Liu, Jinbao Autophagy Research Paper Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly understood. Here, we report an unexpected role for copper in promoting ferroptotic cell death, but not cuproptosis, by inducing macroautophagic/autophagic degradation of GPX4. Copper chelators reduce ferroptosis sensitivity but do not inhibit other types of cell death, such as apoptosis, necroptosis, and alkaliptosis. Conversely, exogenous copper increases GPX4 ubiquitination and the formation of GPX4 aggregates by directly binding to GPX4 protein cysteines C107 and C148. TAX1BP1 (Tax1 binding protein 1) then acts as an autophagic receptor for GPX4 degradation and subsequent ferroptosis in response to copper stress. Consequently, copper enhances ferroptosis-mediated tumor suppression in a mouse model of pancreatic cancer tumor, whereas copper chelators attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into the link between metal stress and autophagy-dependent cell death. Abbreviations: CALCOCO2, calcium binding and coiled-coil domain 2; GPX4, glutathione peroxidase 4; MAP1LC3A/B, microtubule associated protein 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear receptor coactivator 4; OPTN, optineurin; PDAC, pancreatic ductal adenocarcinoma; RIPK1, receptor interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member 1; SQSTM1, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TM, tetrathiomolybdate. Taylor & Francis 2023-01-12 /pmc/articles/PMC10283421/ /pubmed/36622894 http://dx.doi.org/10.1080/15548627.2023.2165323 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper
Xue, Qian
Yan, Ding
Chen, Xi
Li, Xiaofen
Kang, Rui
Klionsky, Daniel J.
Kroemer, Guido
Chen, Xin
Tang, Daolin
Liu, Jinbao
Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title_full Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title_fullStr Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title_full_unstemmed Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title_short Copper-dependent autophagic degradation of GPX4 drives ferroptosis
title_sort copper-dependent autophagic degradation of gpx4 drives ferroptosis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10283421/
https://www.ncbi.nlm.nih.gov/pubmed/36622894
http://dx.doi.org/10.1080/15548627.2023.2165323
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