S-Nitrosation of Protein Phosphatase 1 Mediates Alcohol-Induced Ciliary Dysfunction

Authors

Michael E. Price, University of Nebraska Medical CenterFollow
Adam J. Case, University of Nebraska Medical CenterFollow
Jacqueline A. Pavlik, University of Nebraska Medical CenterFollow
Jane M. DeVasure, University of Nebraska Medical CenterFollow
Todd A. Wyatt, twyatt@unmc.eduFollow
Matthew C. Zimmerman, University of Nebraska Medical CenterFollow
Joseph H. Sisson, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Scientific Reports

Publication Date

2018

Volume

8

Abstract

Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to β-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.

DOI Link

10.1038/s41598-018-27924-x

ISSN

2045-2322

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Price, Michael E.; Case, Adam J.; Pavlik, Jacqueline A.; DeVasure, Jane M.; Wyatt, Todd A.; Zimmerman, Matthew C.; and Sisson, Joseph H., "S-Nitrosation of Protein Phosphatase 1 Mediates Alcohol-Induced Ciliary Dysfunction" (2018). Journal Articles: Cellular & Integrative Physiology. 30.
https://digitalcommons.unmc.edu/com_cell_articles/30