Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy
Autor(a) principal: | |
---|---|
Data de Publicação: | 2022 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/144140 |
Resumo: | Seipin is encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and FLD1/SEI1 in yeast. The gain-of-function N88S mutation in the BSCL2 gene was identified in a cohort of autosomal dominant motor neuron diseases (MNDs) collectively known as seipinopathies. Previous work has shown that this mutation disrupts N-glycosylation, leading to the formation of inclusion bodies (IBs) and contributing to severe Endoplasmic Reticulum (ER) stress and cell death. In this work, we established a humanized yeast model of N88S seipinopathy that recapitulated the formation of IBs and activation of the unfolded protein response (UPR) observed in mammalian systems. Autophagy and the Hrd1-mediated endoplasmic reticulum-associated degradation (ERAD) were fully functional in cells expressing mutant homomers and WT-mutant heteromers of seipin, discarding the possibility that mutant seipin accumulate due to impaired protein quality control systems. Importantly, the N88S seipin form IBs that appear to induce changes in ER morphology, in association with Kar2 chaperone and the Hsp104 disaggregase. For the first time, we have determined that N88S homo-oligomers expressing cells present reduced viability, decreased antioxidant activity and increased oxidative damage associated with loss of mitochondrial membrane potential, higher reactive oxygen species (ROS) levels and lipid peroxidation. This was correlated with the activation of oxidative stress sensor Yap1. Moreover, activation of ERAD and UPR quality control mechanisms were essential for proper cell growth, and crucial to prevent excessive accumulation of ROS in cells expressing N88S homomers solely. Overall, this study provides new insights into the molecular underpinnings of these rare diseases and offers novel targets for potential pharmacological intervention. |
id |
RCAP_32dae301c0bb8de7ddadbea1a12b6bfa |
---|---|
oai_identifier_str |
oai:repositorio-aberto.up.pt:10216/144140 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathyEndoplasmic reticulum stressInclusion bodiesMotor neuron diseaseN88S seipinopathyOxidative stressSaccharomyces cerevisiaeSeipinSeipin is encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and FLD1/SEI1 in yeast. The gain-of-function N88S mutation in the BSCL2 gene was identified in a cohort of autosomal dominant motor neuron diseases (MNDs) collectively known as seipinopathies. Previous work has shown that this mutation disrupts N-glycosylation, leading to the formation of inclusion bodies (IBs) and contributing to severe Endoplasmic Reticulum (ER) stress and cell death. In this work, we established a humanized yeast model of N88S seipinopathy that recapitulated the formation of IBs and activation of the unfolded protein response (UPR) observed in mammalian systems. Autophagy and the Hrd1-mediated endoplasmic reticulum-associated degradation (ERAD) were fully functional in cells expressing mutant homomers and WT-mutant heteromers of seipin, discarding the possibility that mutant seipin accumulate due to impaired protein quality control systems. Importantly, the N88S seipin form IBs that appear to induce changes in ER morphology, in association with Kar2 chaperone and the Hsp104 disaggregase. For the first time, we have determined that N88S homo-oligomers expressing cells present reduced viability, decreased antioxidant activity and increased oxidative damage associated with loss of mitochondrial membrane potential, higher reactive oxygen species (ROS) levels and lipid peroxidation. This was correlated with the activation of oxidative stress sensor Yap1. Moreover, activation of ERAD and UPR quality control mechanisms were essential for proper cell growth, and crucial to prevent excessive accumulation of ROS in cells expressing N88S homomers solely. Overall, this study provides new insights into the molecular underpinnings of these rare diseases and offers novel targets for potential pharmacological intervention.Elsevier2022-11-012022-11-01T00:00:00Z2023-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/144140eng0891-584910.1016/j.freeradbiomed.2022.09.009Nogueira, VChang, CKLan, CYPereira, CCosta, VTeixeira, Vinfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T14:24:06Zoai:repositorio-aberto.up.pt:10216/144140Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:00:28.508798Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
title |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
spellingShingle |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy Nogueira, V Endoplasmic reticulum stress Inclusion bodies Motor neuron disease N88S seipinopathy Oxidative stress Saccharomyces cerevisiae Seipin |
title_short |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
title_full |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
title_fullStr |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
title_full_unstemmed |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
title_sort |
Causative links between ER stress and oxidative damage in a yeast model of human N88S seipinopathy |
author |
Nogueira, V |
author_facet |
Nogueira, V Chang, CK Lan, CY Pereira, C Costa, V Teixeira, V |
author_role |
author |
author2 |
Chang, CK Lan, CY Pereira, C Costa, V Teixeira, V |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
Nogueira, V Chang, CK Lan, CY Pereira, C Costa, V Teixeira, V |
dc.subject.por.fl_str_mv |
Endoplasmic reticulum stress Inclusion bodies Motor neuron disease N88S seipinopathy Oxidative stress Saccharomyces cerevisiae Seipin |
topic |
Endoplasmic reticulum stress Inclusion bodies Motor neuron disease N88S seipinopathy Oxidative stress Saccharomyces cerevisiae Seipin |
description |
Seipin is encoded by the gene Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and FLD1/SEI1 in yeast. The gain-of-function N88S mutation in the BSCL2 gene was identified in a cohort of autosomal dominant motor neuron diseases (MNDs) collectively known as seipinopathies. Previous work has shown that this mutation disrupts N-glycosylation, leading to the formation of inclusion bodies (IBs) and contributing to severe Endoplasmic Reticulum (ER) stress and cell death. In this work, we established a humanized yeast model of N88S seipinopathy that recapitulated the formation of IBs and activation of the unfolded protein response (UPR) observed in mammalian systems. Autophagy and the Hrd1-mediated endoplasmic reticulum-associated degradation (ERAD) were fully functional in cells expressing mutant homomers and WT-mutant heteromers of seipin, discarding the possibility that mutant seipin accumulate due to impaired protein quality control systems. Importantly, the N88S seipin form IBs that appear to induce changes in ER morphology, in association with Kar2 chaperone and the Hsp104 disaggregase. For the first time, we have determined that N88S homo-oligomers expressing cells present reduced viability, decreased antioxidant activity and increased oxidative damage associated with loss of mitochondrial membrane potential, higher reactive oxygen species (ROS) levels and lipid peroxidation. This was correlated with the activation of oxidative stress sensor Yap1. Moreover, activation of ERAD and UPR quality control mechanisms were essential for proper cell growth, and crucial to prevent excessive accumulation of ROS in cells expressing N88S homomers solely. Overall, this study provides new insights into the molecular underpinnings of these rare diseases and offers novel targets for potential pharmacological intervention. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-01 2022-11-01T00:00:00Z 2023-11-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/10216/144140 |
url |
https://hdl.handle.net/10216/144140 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0891-5849 10.1016/j.freeradbiomed.2022.09.009 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799135928385536000 |