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HOIP modulates the stability of GPx4 by linear ubiquitination

LUBAC-mediated linear ubiquitination plays a pivotal role in regulation of cell death and inflammatory pathways. Genetic deficiency in LUBAC components leads to severe immune dysfunction or embryonic lethality. LUBAC has been extensively studied for its role in mediating TNF signaling. However, Tnfr...

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Autores principales: Dong, Kangyun, Wei, Ran, Jin, Taijie, Zhang, Mengmeng, Shen, Jiali, Xiang, Huaijiang, Shan, Bing, Yuan, Junying, Li, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636971/
https://www.ncbi.nlm.nih.gov/pubmed/36279464
http://dx.doi.org/10.1073/pnas.2214227119
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author Dong, Kangyun
Wei, Ran
Jin, Taijie
Zhang, Mengmeng
Shen, Jiali
Xiang, Huaijiang
Shan, Bing
Yuan, Junying
Li, Ying
author_facet Dong, Kangyun
Wei, Ran
Jin, Taijie
Zhang, Mengmeng
Shen, Jiali
Xiang, Huaijiang
Shan, Bing
Yuan, Junying
Li, Ying
author_sort Dong, Kangyun
collection PubMed
description LUBAC-mediated linear ubiquitination plays a pivotal role in regulation of cell death and inflammatory pathways. Genetic deficiency in LUBAC components leads to severe immune dysfunction or embryonic lethality. LUBAC has been extensively studied for its role in mediating TNF signaling. However, Tnfr1 knockout is not able to fully rescue the embryonic lethality of LUBAC deficiency, suggesting that LUBAC may modify additional key cellular substrates in promoting cell survival. GPx4 is an important selenoprotein involved in regulating cellular redox homeostasis in defense against lipid peroxidation-mediated cell death known as ferroptosis. Here we demonstrate that LUBAC deficiency sensitizes to ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation. LUBAC binds and stabilizes GPx4 by modulating its linear ubiquitination both in normal condition and under oxidative stress. Our findings identify GPx4 as a key substrate of LUBAC and a previously unrecognized role of LUBAC-mediated linear ubiquitination in regulating cellular redox status and cell death.
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spelling pubmed-96369712023-04-24 HOIP modulates the stability of GPx4 by linear ubiquitination Dong, Kangyun Wei, Ran Jin, Taijie Zhang, Mengmeng Shen, Jiali Xiang, Huaijiang Shan, Bing Yuan, Junying Li, Ying Proc Natl Acad Sci U S A Biological Sciences LUBAC-mediated linear ubiquitination plays a pivotal role in regulation of cell death and inflammatory pathways. Genetic deficiency in LUBAC components leads to severe immune dysfunction or embryonic lethality. LUBAC has been extensively studied for its role in mediating TNF signaling. However, Tnfr1 knockout is not able to fully rescue the embryonic lethality of LUBAC deficiency, suggesting that LUBAC may modify additional key cellular substrates in promoting cell survival. GPx4 is an important selenoprotein involved in regulating cellular redox homeostasis in defense against lipid peroxidation-mediated cell death known as ferroptosis. Here we demonstrate that LUBAC deficiency sensitizes to ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation. LUBAC binds and stabilizes GPx4 by modulating its linear ubiquitination both in normal condition and under oxidative stress. Our findings identify GPx4 as a key substrate of LUBAC and a previously unrecognized role of LUBAC-mediated linear ubiquitination in regulating cellular redox status and cell death. National Academy of Sciences 2022-10-24 2022-11-01 /pmc/articles/PMC9636971/ /pubmed/36279464 http://dx.doi.org/10.1073/pnas.2214227119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Dong, Kangyun
Wei, Ran
Jin, Taijie
Zhang, Mengmeng
Shen, Jiali
Xiang, Huaijiang
Shan, Bing
Yuan, Junying
Li, Ying
HOIP modulates the stability of GPx4 by linear ubiquitination
title HOIP modulates the stability of GPx4 by linear ubiquitination
title_full HOIP modulates the stability of GPx4 by linear ubiquitination
title_fullStr HOIP modulates the stability of GPx4 by linear ubiquitination
title_full_unstemmed HOIP modulates the stability of GPx4 by linear ubiquitination
title_short HOIP modulates the stability of GPx4 by linear ubiquitination
title_sort hoip modulates the stability of gpx4 by linear ubiquitination
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636971/
https://www.ncbi.nlm.nih.gov/pubmed/36279464
http://dx.doi.org/10.1073/pnas.2214227119
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