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Bilirubin neurotoxicity is associated with proteasome inhibition

The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin–proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal...

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Autores principales: Huang, Hongbiao, Guo, Mingxing, Liu, Ningning, Zhao, Chong, Chen, Haoyu, Wang, Xiaoli, Liao, Siyan, Zhou, Ping, Liao, Yuning, Chen, Xin, Lan, Xiaoying, Chen, Jinghong, Xu, Dacai, Li, Xiaofen, Shi, Xianping, Yu, Li, Nie, Yuqiang, Wang, Xuejun, Zhang, Chang-E, Liu, Jinbao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520929/
https://www.ncbi.nlm.nih.gov/pubmed/28617443
http://dx.doi.org/10.1038/cddis.2017.274
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author Huang, Hongbiao
Guo, Mingxing
Liu, Ningning
Zhao, Chong
Chen, Haoyu
Wang, Xiaoli
Liao, Siyan
Zhou, Ping
Liao, Yuning
Chen, Xin
Lan, Xiaoying
Chen, Jinghong
Xu, Dacai
Li, Xiaofen
Shi, Xianping
Yu, Li
Nie, Yuqiang
Wang, Xuejun
Zhang, Chang-E
Liu, Jinbao
author_facet Huang, Hongbiao
Guo, Mingxing
Liu, Ningning
Zhao, Chong
Chen, Haoyu
Wang, Xiaoli
Liao, Siyan
Zhou, Ping
Liao, Yuning
Chen, Xin
Lan, Xiaoying
Chen, Jinghong
Xu, Dacai
Li, Xiaofen
Shi, Xianping
Yu, Li
Nie, Yuqiang
Wang, Xuejun
Zhang, Chang-E
Liu, Jinbao
author_sort Huang, Hongbiao
collection PubMed
description The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin–proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity.
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spelling pubmed-55209292017-07-27 Bilirubin neurotoxicity is associated with proteasome inhibition Huang, Hongbiao Guo, Mingxing Liu, Ningning Zhao, Chong Chen, Haoyu Wang, Xiaoli Liao, Siyan Zhou, Ping Liao, Yuning Chen, Xin Lan, Xiaoying Chen, Jinghong Xu, Dacai Li, Xiaofen Shi, Xianping Yu, Li Nie, Yuqiang Wang, Xuejun Zhang, Chang-E Liu, Jinbao Cell Death Dis Original Article The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin–proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity. Nature Publishing Group 2017-06 2017-06-15 /pmc/articles/PMC5520929/ /pubmed/28617443 http://dx.doi.org/10.1038/cddis.2017.274 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Huang, Hongbiao
Guo, Mingxing
Liu, Ningning
Zhao, Chong
Chen, Haoyu
Wang, Xiaoli
Liao, Siyan
Zhou, Ping
Liao, Yuning
Chen, Xin
Lan, Xiaoying
Chen, Jinghong
Xu, Dacai
Li, Xiaofen
Shi, Xianping
Yu, Li
Nie, Yuqiang
Wang, Xuejun
Zhang, Chang-E
Liu, Jinbao
Bilirubin neurotoxicity is associated with proteasome inhibition
title Bilirubin neurotoxicity is associated with proteasome inhibition
title_full Bilirubin neurotoxicity is associated with proteasome inhibition
title_fullStr Bilirubin neurotoxicity is associated with proteasome inhibition
title_full_unstemmed Bilirubin neurotoxicity is associated with proteasome inhibition
title_short Bilirubin neurotoxicity is associated with proteasome inhibition
title_sort bilirubin neurotoxicity is associated with proteasome inhibition
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520929/
https://www.ncbi.nlm.nih.gov/pubmed/28617443
http://dx.doi.org/10.1038/cddis.2017.274
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