The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells

Abstract Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed...

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Autores principales:	Yanmin Zhong, Xin Li, Xixun Du, Mingxia Bi, Fengtong Ma, Junxia Xie, Hong Jiang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/22540776606441e0bc5953c1c4410373
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spelling	oai:doaj.org-article:22540776606441e0bc5953c1c44103732021-12-02T18:48:01ZThe S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells10.1038/s41598-020-72630-22045-2322https://doaj.org/article/22540776606441e0bc5953c1c44103732020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-72630-2https://doaj.org/toc/2045-2322Abstract Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed in PD. However, the effects of S-nitrosylation on the E3 ubiquitin ligase activity of parkin for the ubiquitination of DMT1 in PD are largely unknown. To elucidate the role of S-nitrosylated parkin and DMT1 in PD, SH-SY5Y cells were transfected with parkin, being treated with S-nitrosoglutathione (GSNO) and 1-methyl-4-phenylpyridinium (MPP+). The results showed increased levels of oxidized nitric oxide (NO) and S-nitrosylated parkin after the treatment of GSNO and MPP+ in parkin-transfected cells. Consistently, increased levels of DMT1, iron uptake and cell viability were observed. Interestingly, inhibition of S-nitrosylated parkin reduced the level of DMT1. Further, S-nitrosylation of parkin significantly inhibited the ubiquitination of DMT1. When HEK293T cells were transfected with plasmid of parkin with single site mutation (Cys241A, Cys260A, Cys323A), ubiquitination of DMT1 was also inhibited. However, the cells cotransfected with plasmids containing all three mutations, GSNO treatment did not affect the ubiquitination of DMT1. The expression of SNO-parkin and DMT1 protein in substantia nigra increased significantly gradually after 2 h, 4 h and 24 h with MPTP injection. These results indicate that the S-nitrosylation of parkin inhibits its E3 ubiquitin ligase activity for the ubiquitination of DMT1, which contributes to iron accumulation and degenerative process in PD. Targeted S-nitrosylation could provide a potential therapeutic strategy against PD.Yanmin ZhongXin LiXixun DuMingxia BiFengtong MaJunxia XieHong JiangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yanmin Zhong Xin Li Xixun Du Mingxia Bi Fengtong Ma Junxia Xie Hong Jiang The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
description	Abstract Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed in PD. However, the effects of S-nitrosylation on the E3 ubiquitin ligase activity of parkin for the ubiquitination of DMT1 in PD are largely unknown. To elucidate the role of S-nitrosylated parkin and DMT1 in PD, SH-SY5Y cells were transfected with parkin, being treated with S-nitrosoglutathione (GSNO) and 1-methyl-4-phenylpyridinium (MPP+). The results showed increased levels of oxidized nitric oxide (NO) and S-nitrosylated parkin after the treatment of GSNO and MPP+ in parkin-transfected cells. Consistently, increased levels of DMT1, iron uptake and cell viability were observed. Interestingly, inhibition of S-nitrosylated parkin reduced the level of DMT1. Further, S-nitrosylation of parkin significantly inhibited the ubiquitination of DMT1. When HEK293T cells were transfected with plasmid of parkin with single site mutation (Cys241A, Cys260A, Cys323A), ubiquitination of DMT1 was also inhibited. However, the cells cotransfected with plasmids containing all three mutations, GSNO treatment did not affect the ubiquitination of DMT1. The expression of SNO-parkin and DMT1 protein in substantia nigra increased significantly gradually after 2 h, 4 h and 24 h with MPTP injection. These results indicate that the S-nitrosylation of parkin inhibits its E3 ubiquitin ligase activity for the ubiquitination of DMT1, which contributes to iron accumulation and degenerative process in PD. Targeted S-nitrosylation could provide a potential therapeutic strategy against PD.
format	article
author	Yanmin Zhong Xin Li Xixun Du Mingxia Bi Fengtong Ma Junxia Xie Hong Jiang
author_facet	Yanmin Zhong Xin Li Xixun Du Mingxia Bi Fengtong Ma Junxia Xie Hong Jiang
author_sort	Yanmin Zhong
title	The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
title_short	The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
title_full	The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
title_fullStr	The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
title_full_unstemmed	The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells
title_sort	s-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in mpp+-treated sh-sy5y cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/22540776606441e0bc5953c1c4410373
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The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP+-treated SH-SY5Y cells

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