Journal article
FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity
Chronic obstructive pulmonary disease, Vol.21(1), p.2342797
12/2024
DOI: 10.1080/15412555.2024.2342797
PMID: 38712759
Abstract
To investigate the effects of cigarette smoke (CS) on Serine/Threonine Kinase 11 (STK11) and to determine STK11's role in CS-induced airway epithelial cell cytotoxicity.
STK11 expression levels in the lung tissues of smokers with or without COPD and mice exposed to CS or room air (RA) were determined by immunoblotting and RT-PCR. BEAS-2Bs-human bronchial airway epithelial cells were exposed to CS extract (CSE), and the changes in STK11 expression levels were determined by immunoblotting and RT-PCR. BEAS-2B cells were transfected with STK11-specific siRNA or STK11 expression plasmid, and the effects of CSE on airway epithelial cell cytotoxicity were measured. To determine the specific STK11 degradation-proteolytic pathway, BEAS-2Bs were treated with cycloheximide alone or combined with MG132 or leupeptin. Finally, to identify the F-box protein mediating the STK11 degradation, a screening assay was performed using transfection with a panel of FBXL E3 ligase subunits.
STK11 protein levels were significantly decreased in the lung tissues of smokers with COPD relative to smokers without COPD. STK11 protein levels were also significantly decreased in mouse lung tissues exposed to CS compared to RA. Exposure to CSE shortened the STK11 mRNA and protein half-life to 4 h in BEAS-2B cells. STK11 protein overexpression attenuated the CSE-induced cytotoxicity; in contrast, its knockdown augmented CSE-induced cytotoxicity. FBXL19 mediates CSE-induced STK11 protein degradation
the ubiquitin-proteasome pathway in cultured BEAS-2B cells. FBXL19 overexpression led to accelerated STK11 ubiquitination and degradation in a dose-dependent manner.
Our results suggest that CSE enhances the degradation of STK11 protein in airway epithelial cells
the FBXL19-mediated ubiquitin-proteasomal pathway, leading to augmented cell death.HIGHLIGHTSLung tissues of COPD-smokers exhibited a decreased STK11 RNA and protein expression.STK11 overexpression attenuates CS-induced airway epithelial cell cytotoxicity.STK11 depletion augments CS-induced airway epithelial cell cytotoxicity.CS diminishes STK11 via FBXL19-mediated ubiquitin-proteasome degradation.
Details
- Title: Subtitle
- FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity
- Creators
- Xiuying Li - University of PittsburghSowmya P Lakshmi - University of PittsburghKiyoshi Uemasu - University of PittsburghZachary Lane - University of PittsburghRajan T Reddy - University of PittsburghDivay Chandra - University of PittsburghChunbin Zou - University of PittsburghYu Jiang - University of PittsburghToru Nyunoya - VA Pittsburgh Healthcare System
- Resource Type
- Journal article
- Publication Details
- Chronic obstructive pulmonary disease, Vol.21(1), p.2342797
- DOI
- 10.1080/15412555.2024.2342797
- PMID
- 38712759
- ISSN
- 1541-2555
- eISSN
- 1541-2563
- Grant note
- I01 BX006096 / BLRD VA R01 HL153400 / NHLBI NIH HHS R01 HL142997 / NHLBI NIH HHS I01 CX001048 / CSRD VA R01 HL149719 / NHLBI NIH HHS I01 CX000105 / CSRD VA R01 GM132127 / NIGMS NIH HHS
- Language
- English
- Date published
- 12/2024
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985214171802771
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