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The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα
An intact lung epithelial barrier is essential for lung homeostasis. The Na(+), K(+)-ATPase (NKA), primarily serving as an ion transporter, also regulates epithelial barrier function via modulation of tight junctions. However, the underlying mechanism is not well understood. Here, we show that overe...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934944/ https://www.ncbi.nlm.nih.gov/pubmed/33507884 http://dx.doi.org/10.1172/jci.insight.134881 |
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author | Bai, Haiqing Zhou, Rui Barravecchia, Michael Norman, Rosemary Friedman, Alan Yu, Deborah Lin, Xin Young, Jennifer L. Dean, David A. |
author_facet | Bai, Haiqing Zhou, Rui Barravecchia, Michael Norman, Rosemary Friedman, Alan Yu, Deborah Lin, Xin Young, Jennifer L. Dean, David A. |
author_sort | Bai, Haiqing |
collection | PubMed |
description | An intact lung epithelial barrier is essential for lung homeostasis. The Na(+), K(+)-ATPase (NKA), primarily serving as an ion transporter, also regulates epithelial barrier function via modulation of tight junctions. However, the underlying mechanism is not well understood. Here, we show that overexpression of the NKA β1 subunit upregulates the expression of tight junction proteins, leading to increased alveolar epithelial barrier function by an ion transport–independent mechanism. Using IP and mass spectrometry, we identified a number of unknown protein interactions of the β1 subunit, including a top candidate, myotonic dystrophy kinase–related cdc42-binding kinase α (MRCKα), which is a protein kinase known to regulate peripheral actin formation. Using a doxycycline-inducible gene expression system, we demonstrated that MRCKα and its downstream activation of myosin light chain is required for the regulation of alveolar barrier function by the NKA β1 subunit. Importantly, MRCKα is expressed in both human airways and alveoli and has reduced expression in patients with acute respiratory distress syndrome (ARDS), a lung illness that can be caused by multiple direct and indirect insults, including the infection of influenza virus and SARS-CoV-2. Our results have elucidated a potentially novel mechanism by which NKA regulates epithelial tight junctions and have identified potential drug targets for treating ARDS and other pulmonary diseases that are caused by barrier dysfunction. |
format | Online Article Text |
id | pubmed-7934944 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-79349442021-03-09 The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα Bai, Haiqing Zhou, Rui Barravecchia, Michael Norman, Rosemary Friedman, Alan Yu, Deborah Lin, Xin Young, Jennifer L. Dean, David A. JCI Insight Research Article An intact lung epithelial barrier is essential for lung homeostasis. The Na(+), K(+)-ATPase (NKA), primarily serving as an ion transporter, also regulates epithelial barrier function via modulation of tight junctions. However, the underlying mechanism is not well understood. Here, we show that overexpression of the NKA β1 subunit upregulates the expression of tight junction proteins, leading to increased alveolar epithelial barrier function by an ion transport–independent mechanism. Using IP and mass spectrometry, we identified a number of unknown protein interactions of the β1 subunit, including a top candidate, myotonic dystrophy kinase–related cdc42-binding kinase α (MRCKα), which is a protein kinase known to regulate peripheral actin formation. Using a doxycycline-inducible gene expression system, we demonstrated that MRCKα and its downstream activation of myosin light chain is required for the regulation of alveolar barrier function by the NKA β1 subunit. Importantly, MRCKα is expressed in both human airways and alveoli and has reduced expression in patients with acute respiratory distress syndrome (ARDS), a lung illness that can be caused by multiple direct and indirect insults, including the infection of influenza virus and SARS-CoV-2. Our results have elucidated a potentially novel mechanism by which NKA regulates epithelial tight junctions and have identified potential drug targets for treating ARDS and other pulmonary diseases that are caused by barrier dysfunction. American Society for Clinical Investigation 2021-02-22 /pmc/articles/PMC7934944/ /pubmed/33507884 http://dx.doi.org/10.1172/jci.insight.134881 Text en © 2021 Bai et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Bai, Haiqing Zhou, Rui Barravecchia, Michael Norman, Rosemary Friedman, Alan Yu, Deborah Lin, Xin Young, Jennifer L. Dean, David A. The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title | The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title_full | The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title_fullStr | The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title_full_unstemmed | The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title_short | The Na(+), K(+)-ATPase β1 subunit regulates epithelial tight junctions via MRCKα |
title_sort | na(+), k(+)-atpase β1 subunit regulates epithelial tight junctions via mrckα |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934944/ https://www.ncbi.nlm.nih.gov/pubmed/33507884 http://dx.doi.org/10.1172/jci.insight.134881 |
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