@article{10.1172/jci.insight.125895, author = {Rama K. Mallampalli AND Xiuying Li AND Jun-Ho Jang AND Tomasz Kaminski AND Aki Hoji AND Tiffany Coon AND Divay Chandra AND Starr Welty AND Yaqun Teng AND John Sembrat AND Mauricio Rojas AND Yutong Zhao AND Robert Lafyatis AND Chunbin Zou AND Frank Sciurba AND Prithu Sundd AND Li Lan AND Toru Nyunoya}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Cigarette smoke exposure enhances transforming acidic coiled-coil–containing protein 2 turnover and thereby promotes emphysema}, year = {2020}, month = {2}, volume = {5}, url = {https://insight.jci.org/articles/view/125895}, abstract = {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.}, number = {2}, doi = {10.1172/jci.insight.125895}, url = {https://doi.org/10.1172/jci.insight.125895}, }