Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF

Abstract The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Susan Monkley, Catherine Overed-Sayer, Helen Parfrey, Doris Rassl, Damian Crowther, Leire Escudero-Ibarz, Nicola Davis, Alan Carruthers, Richard Berks, Marisa Coetzee, Ewa Kolosionek, Maria Karlsson, Leia R. Griffin, Maryam Clausen, Graham Belfield, Cory M. Hogaboam, Lynne A. Murray
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/140262651e644238bf169dc86b4b8869
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:140262651e644238bf169dc86b4b8869
record_format	dspace
spelling	oai:doaj.org-article:140262651e644238bf169dc86b4b88692021-11-08T10:51:48ZSensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF10.1038/s41598-021-00769-72045-2322https://doaj.org/article/140262651e644238bf169dc86b4b88692021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00769-7https://doaj.org/toc/2045-2322Abstract The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.Susan MonkleyCatherine Overed-SayerHelen ParfreyDoris RasslDamian CrowtherLeire Escudero-IbarzNicola DavisAlan CarruthersRichard BerksMarisa CoetzeeEwa KolosionekMaria KarlssonLeia R. GriffinMaryam ClausenGraham BelfieldCory M. HogaboamLynne A. MurrayNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Susan Monkley Catherine Overed-Sayer Helen Parfrey Doris Rassl Damian Crowther Leire Escudero-Ibarz Nicola Davis Alan Carruthers Richard Berks Marisa Coetzee Ewa Kolosionek Maria Karlsson Leia R. Griffin Maryam Clausen Graham Belfield Cory M. Hogaboam Lynne A. Murray Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
description	Abstract The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.
format	article
author	Susan Monkley Catherine Overed-Sayer Helen Parfrey Doris Rassl Damian Crowther Leire Escudero-Ibarz Nicola Davis Alan Carruthers Richard Berks Marisa Coetzee Ewa Kolosionek Maria Karlsson Leia R. Griffin Maryam Clausen Graham Belfield Cory M. Hogaboam Lynne A. Murray
author_facet	Susan Monkley Catherine Overed-Sayer Helen Parfrey Doris Rassl Damian Crowther Leire Escudero-Ibarz Nicola Davis Alan Carruthers Richard Berks Marisa Coetzee Ewa Kolosionek Maria Karlsson Leia R. Griffin Maryam Clausen Graham Belfield Cory M. Hogaboam Lynne A. Murray
author_sort	Susan Monkley
title	Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
title_short	Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
title_full	Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
title_fullStr	Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
title_full_unstemmed	Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF
title_sort	sensitization of the upr by loss of ppp1r15a promotes fibrosis and senescence in ipf
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/140262651e644238bf169dc86b4b8869
work_keys_str_mv	AT susanmonkley sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT catherineoveredsayer sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT helenparfrey sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT dorisrassl sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT damiancrowther sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT leireescuderoibarz sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT nicoladavis sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT alancarruthers sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT richardberks sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT marisacoetzee sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT ewakolosionek sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT mariakarlsson sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT leiargriffin sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT maryamclausen sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT grahambelfield sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT corymhogaboam sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf AT lynneamurray sensitizationoftheuprbylossofppp1r15apromotesfibrosisandsenescenceinipf
_version_	1718442497822162944

Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF

Ejemplares similares