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Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain

BACKGROUND: Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget’s disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Ke...

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Autores principales: Tanji, Kunikazu, Miki, Yasuo, Ozaki, Taku, Maruyama, Atsushi, Yoshida, Hidemi, Mimura, Junsei, Matsumiya, Tomoh, Mori, Fumiaki, Imaizumi, Tadaatsu, Itoh, Ken, Kakita, Akiyoshi, Takahashi, Hitoshi, Wakabayashi, Koichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035093/
https://www.ncbi.nlm.nih.gov/pubmed/24886973
http://dx.doi.org/10.1186/2051-5960-2-50
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author Tanji, Kunikazu
Miki, Yasuo
Ozaki, Taku
Maruyama, Atsushi
Yoshida, Hidemi
Mimura, Junsei
Matsumiya, Tomoh
Mori, Fumiaki
Imaizumi, Tadaatsu
Itoh, Ken
Kakita, Akiyoshi
Takahashi, Hitoshi
Wakabayashi, Koichi
author_facet Tanji, Kunikazu
Miki, Yasuo
Ozaki, Taku
Maruyama, Atsushi
Yoshida, Hidemi
Mimura, Junsei
Matsumiya, Tomoh
Mori, Fumiaki
Imaizumi, Tadaatsu
Itoh, Ken
Kakita, Akiyoshi
Takahashi, Hitoshi
Wakabayashi, Koichi
author_sort Tanji, Kunikazu
collection PubMed
description BACKGROUND: Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget’s disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions. RESULTS: To answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer’s disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349. CONCLUSION: These results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2051-5960-2-50) contains supplementary material, which is available to authorized users.
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spelling pubmed-40350932014-06-06 Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain Tanji, Kunikazu Miki, Yasuo Ozaki, Taku Maruyama, Atsushi Yoshida, Hidemi Mimura, Junsei Matsumiya, Tomoh Mori, Fumiaki Imaizumi, Tadaatsu Itoh, Ken Kakita, Akiyoshi Takahashi, Hitoshi Wakabayashi, Koichi Acta Neuropathol Commun Research BACKGROUND: Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget’s disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions. RESULTS: To answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer’s disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349. CONCLUSION: These results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2051-5960-2-50) contains supplementary material, which is available to authorized users. BioMed Central 2014-05-03 /pmc/articles/PMC4035093/ /pubmed/24886973 http://dx.doi.org/10.1186/2051-5960-2-50 Text en © TANJI et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Tanji, Kunikazu
Miki, Yasuo
Ozaki, Taku
Maruyama, Atsushi
Yoshida, Hidemi
Mimura, Junsei
Matsumiya, Tomoh
Mori, Fumiaki
Imaizumi, Tadaatsu
Itoh, Ken
Kakita, Akiyoshi
Takahashi, Hitoshi
Wakabayashi, Koichi
Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title_full Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title_fullStr Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title_full_unstemmed Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title_short Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain
title_sort phosphorylation of serine 349 of p62 in alzheimer’s disease brain
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035093/
https://www.ncbi.nlm.nih.gov/pubmed/24886973
http://dx.doi.org/10.1186/2051-5960-2-50
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