Cigarette smoke exposure enhances transforming acidic coiled-coil–containing protein 2 turnover and thereby promotes emphysema
| Autor: | Yaqun Teng, Yutong Zhao, Li Lan, Mauricio Rojas, Robert Lafyatis, Starr Welty, Chunbin Zou, Jun-Ho Jang, Aki Hoji, Tomasz W. Kaminski, John Sembrat, Toru Nyunoya, Frank C. Sciurba, Xiuying Li, Prithu Sundd, Rama K. Mallampalli, Divay Chandra, Tiffany A. Coon |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Proteasome Endopeptidase Complex DNA Repair DNA repair DNA damage Ubiquitin-Protein Ligases Protein subunit Apoptosis Cell Line Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Smoke Tobacco Animals Humans Lung Aged Emphysema Mice Knockout biology Chemistry Tumor Suppressor Proteins Smoking TACC2 Epithelial Cells General Medicine Middle Aged respiratory tract diseases Ubiquitin ligase Cell biology Mice Inbred C57BL 030104 developmental biology Pulmonary Emphysema Proteasome 030220 oncology & carcinogenesis Mutagenesis Site-Directed biology.protein Female Carrier Proteins Transcriptome Research Article DNA Damage |
| Zdroj: | JCI Insight. 5 |
| ISSN: | 2379-3708 |
| Popis: | Our integrative genomic and functional analysis identified transforming acidic coiled-coil–containing protein 2 (TACC2) as a chronic obstructive pulmonary disease (COPD) candidate gene. Here, we found that smokers with COPD exhibit a marked decrease in lung TACC2 protein levels relative to smokers without COPD. Single cell RNA sequencing reveals that TACC2 is expressed primarily in lung epithelial cells in normal human lungs. Furthermore, suppression of TACC2 expression impairs the efficiency of homologous recombination repair and augments spontaneous and cigarette smoke extract–induced (CSE-induced) DNA damage and cytotoxicity in immortalized human bronchial epithelial cells. By contrast, enforced expression of TACC2 attenuates the CSE effects. We also found that CSE enhances TACC2 degradation via the ubiquitin-proteasome system mediated by the ubiquitin E3 ligase subunit, F box L7. Furthermore, cellularly expressed TACC2 proteins harboring naturally occurring mutations exhibited altered protein lifespan coupled with modified DNA damage repair and cytotoxic responses. CS triggers emphysematous changes accompanied by accumulated DNA damage, apoptosis of alveolar epithelia, and lung inflammation in Tacc2(–/–) compared with Tacc2(+/+) mice. Our results suggest that CS destabilizes TACC2 protein in lung epithelia by the ubiquitin proteasome system, leading to subsequent DNA damage, cytotoxicity, and emphysema. |
| Databáze: | OpenAIRE |
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