RRC ID |
48847
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著者 |
Tominaga T, Goto M, Onoue T, Mizoguchi A, Sugiyama M, Tsunekawa T, Hagiwara D, Morishita Y, Ito Y, Iwama S, Suga H, Banno R, Arima H.
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タイトル |
Sequestosome 1 (SQSTM1/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture.
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ジャーナル |
Neurosci Lett
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Abstract |
Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-eIF2α protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity.
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巻・号 |
656
|
ページ |
103-107
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公開日 |
2017-8-24
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DOI |
10.1016/j.neulet.2017.06.014
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PII |
S0304-3940(17)30494-9
|
PMID |
28619261
|
MeSH |
Animals
Autophagosomes / physiology
Endoplasmic Reticulum Stress*
Hypothalamus / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Protein Folding
Sequestosome-1 Protein / genetics
Sequestosome-1 Protein / metabolism*
Tissue Culture Techniques
Unfolded Protein Response
|
IF |
2.274
|
引用数 |
0
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リソース情報 |
実験動物マウス |
RBRC00806 |