Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome

Abstract Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Althou...

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Autores principales:	Sneha Sitaraman, Cheng-Lun Na, Li Yang, Alyssa Filuta, James P. Bridges, Timothy E. Weaver
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/40d2d9dc7bbd4a109b5a7e6963055bb1
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spelling	oai:doaj.org-article:40d2d9dc7bbd4a109b5a7e6963055bb12021-12-02T15:10:00ZProteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome10.1038/s41598-019-49020-42045-2322https://doaj.org/article/40d2d9dc7bbd4a109b5a7e6963055bb12019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-49020-4https://doaj.org/toc/2045-2322Abstract Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Although pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Partial deletion of RPT3 resulted in 26S proteasome dysfunction, leading to augmented cell stress and cell death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome (ARDS). This study underscores importance of proteasome function in maintenance of AT2 cell homeostasis and supports the need to further investigate the role of proteasome dysfunction in ARDS pathogenesis.Sneha SitaramanCheng-Lun NaLi YangAlyssa FilutaJames P. BridgesTimothy E. WeaverNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-15 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sneha Sitaraman Cheng-Lun Na Li Yang Alyssa Filuta James P. Bridges Timothy E. Weaver Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
description	Abstract Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Although pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Partial deletion of RPT3 resulted in 26S proteasome dysfunction, leading to augmented cell stress and cell death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome (ARDS). This study underscores importance of proteasome function in maintenance of AT2 cell homeostasis and supports the need to further investigate the role of proteasome dysfunction in ARDS pathogenesis.
format	article
author	Sneha Sitaraman Cheng-Lun Na Li Yang Alyssa Filuta James P. Bridges Timothy E. Weaver
author_facet	Sneha Sitaraman Cheng-Lun Na Li Yang Alyssa Filuta James P. Bridges Timothy E. Weaver
author_sort	Sneha Sitaraman
title	Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
title_short	Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
title_full	Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
title_fullStr	Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
title_full_unstemmed	Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
title_sort	proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/40d2d9dc7bbd4a109b5a7e6963055bb1
work_keys_str_mv	AT snehasitaraman proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome AT chenglunna proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome AT liyang proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome AT alyssafiluta proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome AT jamespbridges proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome AT timothyeweaver proteasomedysfunctioninalveolartype2epithelialcellsisassociatedwithacuterespiratorydistresssyndrome
_version_	1718387746641281024

Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome

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