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Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration

Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquiti...

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Autores principales: Wakatsuki, Shuji, Furuno, Akiko, Ohshima, Makiko, Araki, Toshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657170/
https://www.ncbi.nlm.nih.gov/pubmed/26572622
http://dx.doi.org/10.1083/jcb.201506102
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author Wakatsuki, Shuji
Furuno, Akiko
Ohshima, Makiko
Araki, Toshiyuki
author_facet Wakatsuki, Shuji
Furuno, Akiko
Ohshima, Makiko
Araki, Toshiyuki
author_sort Wakatsuki, Shuji
collection PubMed
description Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate–reduced oxidase activity is required for the EGFR-dependent phosphorylation-induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR–ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration.
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spelling pubmed-46571702016-05-23 Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration Wakatsuki, Shuji Furuno, Akiko Ohshima, Makiko Araki, Toshiyuki J Cell Biol Research Articles Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate–reduced oxidase activity is required for the EGFR-dependent phosphorylation-induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR–ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration. The Rockefeller University Press 2015-11-23 /pmc/articles/PMC4657170/ /pubmed/26572622 http://dx.doi.org/10.1083/jcb.201506102 Text en © 2015 Wakatsuki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Wakatsuki, Shuji
Furuno, Akiko
Ohshima, Makiko
Araki, Toshiyuki
Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title_full Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title_fullStr Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title_full_unstemmed Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title_short Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration
title_sort oxidative stress–dependent phosphorylation activates znrf1 to induce neuronal/axonal degeneration
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657170/
https://www.ncbi.nlm.nih.gov/pubmed/26572622
http://dx.doi.org/10.1083/jcb.201506102
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