Cargando…

A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b

A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membra...

Descripción completa

Detalles Bibliográficos
Autores principales: Saito, Shunsuke, Ishikawa, Tokiro, Ninagawa, Satoshi, Okada, Tetsuya, Mori, Kazutoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708084/
https://www.ncbi.nlm.nih.gov/pubmed/36444643
http://dx.doi.org/10.7554/eLife.74805
_version_ 1784840845084590080
author Saito, Shunsuke
Ishikawa, Tokiro
Ninagawa, Satoshi
Okada, Tetsuya
Mori, Kazutoshi
author_facet Saito, Shunsuke
Ishikawa, Tokiro
Ninagawa, Satoshi
Okada, Tetsuya
Mori, Kazutoshi
author_sort Saito, Shunsuke
collection PubMed
description A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above.
format Online
Article
Text
id pubmed-9708084
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-97080842022-11-30 A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b Saito, Shunsuke Ishikawa, Tokiro Ninagawa, Satoshi Okada, Tetsuya Mori, Kazutoshi eLife Cell Biology A causal relationship between endoplasmic reticulum (ER) stress and the development of neurodegenerative diseases remains controversial. Here, we focused on Seipinopathy, a dominant motor neuron disease, based on the finding that its causal gene product, Seipin, is a protein that spans the ER membrane twice. Gain-of-function mutations of Seipin produce non-glycosylated Seipin (ngSeipin), which was previously shown to induce ER stress and apoptosis at both cell and mouse levels albeit with no clarified mechanism. We found that aggregation-prone ngSeipin dominantly inactivated SERCA2b, the major calcium pump in the ER, and decreased the calcium concentration in the ER, leading to ER stress and apoptosis in human colorectal carcinoma-derived cells (HCT116). This inactivation required oligomerization of ngSeipin and direct interaction of the C-terminus of ngSeipin with SERCA2b, and was observed in Seipin-deficient neuroblastoma (SH-SY5Y) cells expressing ngSeipin at an endogenous protein level. Our results thus provide a new direction to the controversy noted above. eLife Sciences Publications, Ltd 2022-11-29 /pmc/articles/PMC9708084/ /pubmed/36444643 http://dx.doi.org/10.7554/eLife.74805 Text en © 2022, Saito et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Saito, Shunsuke
Ishikawa, Tokiro
Ninagawa, Satoshi
Okada, Tetsuya
Mori, Kazutoshi
A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title_full A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title_fullStr A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title_full_unstemmed A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title_short A motor neuron disease-associated mutation produces non-glycosylated Seipin that induces ER stress and apoptosis by inactivating SERCA2b
title_sort motor neuron disease-associated mutation produces non-glycosylated seipin that induces er stress and apoptosis by inactivating serca2b
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9708084/
https://www.ncbi.nlm.nih.gov/pubmed/36444643
http://dx.doi.org/10.7554/eLife.74805
work_keys_str_mv AT saitoshunsuke amotorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT ishikawatokiro amotorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT ninagawasatoshi amotorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT okadatetsuya amotorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT morikazutoshi amotorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT saitoshunsuke motorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT ishikawatokiro motorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT ninagawasatoshi motorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT okadatetsuya motorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b
AT morikazutoshi motorneurondiseaseassociatedmutationproducesnonglycosylatedseipinthatinduceserstressandapoptosisbyinactivatingserca2b