title: Alcohol drivesS-nitrosylation and redox activation of protein phosphatase 1, causing bovine airway cilia dysfunction.
abstract: Individuals with alcohol (ethanol)-use disorders are at increased risk for lung infections, in part, due to defective mucociliary clearance driven by motile cilia in the airways. We recently reported that isolated, demembranated bovine cilia (axonemes) are capable of producing nitric oxide (∙NO) when exposed to biologically relevant concentrations of alcohol. This increased presence of∙NO can lead to proteinS-nitrosylation, a posttranslational modification signaling mechanism involving reversible adduction of nitrosonium cations or∙NO to thiolate or thiyl radicals, respectively, of proteins formingS-nitrosothiols (SNOs). We quantified and compared SNO content between isolated, demembranated axonemes extracted from bovine tracheae, with or without in situ alcohol exposure (100 mM × 24 h). We demonstrate that relevant concentrations of alcohol exposure shift theS-nitrosylation status of key cilia regulatory proteins, including 20-fold increases inS-nitrosylation of proteins that include protein phosphatase 1 (PP1). With the use of an ATP-reactivated axoneme motility system, we demonstrate that alcohol-drivenS-nitrosylation of PP1 is associated with PP1 activation and dysfunction of axoneme motility. These new data demonstrate that alcohol can shift theS-nitrothiol balance at the level of the cilia organelle and highlightS-nitrosylation as a novel signaling mechanism to regulate PP1 and cilia motility.
authors.affiliation: Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Price
authors.affiliation: Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Pavlik
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Shi-Jian
authors.initials: SJ
authors.lastname: Ding
authors.affiliation: Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.|Department of Environmental, Agricultural, and Occupational Health, University of Nebraska Medical Center, Omaha, Nebraska; and.|Research Service, Nebraska-Western Iowa VA Healthcare System, Omaha, Nebraska.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wyatt
authors.affiliation: Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; jsisson@unmc.edu.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Sisson
mesh_terms: D000818:Animals; D054468:Axoneme / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002923:Cilia / Q000187:drug effects / Q000473:pathology*; D000431:Ethanol / Q000633:toxicity*; D015538:Nitrosation; D010084:Oxidation-Reduction / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D020543:Proteome; D000431:Ethanol; D054645:Protein Phosphatase 1
keywords: S-nitrosylation; alcohol; cilia; redox regulation