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TACC2 Protein Mediates Epithelial Cell Survival and Alveolar Integrity Against Cigarette Smoke Exposure
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A7605 - TACC2 Protein Mediates Epithelial Cell Survival and Alveolar Integrity Against Cigarette Smoke Exposure
Author Block: T. Nyunoya1, X. Li1, J. Jang2, C. Zou1, R. Mallampalli3; 1Medicine, University of Pittsburgh, Pittsburgh, PA, United States, 2Allegheny Health Network, Pittsburgh, PA, United States, 3PACCM, UPMC Montefiore, Pittsburgh, PA, United States.
Accumulating evidence suggest a causative role for DNA damage and alveolar cell apoptosis in chronic obstructive pulmonary disease (COPD) pathogenesis. However, the molecular basis for cigarette smoke (CS)-induced DNA damage and apoptosis remains to be elucidated. Our recent integrative analysis identified transforming acidic coiled-coil-containing protein 2 (Tacc2) as a COPD candidate gene. Here, we found that smokers with COPD exhibit a marked decrease in lung TACC2 protein levels as compared with smokers without COPD. CS triggered emphysematous changes accompanied by DNA damage in TACC2-/- compared to TACC2+/+ mice. In human bronchial epithelial cells, CS increased binding of TACC2 to the acetyltransferase, KAT2B, thereby increasing TACC2 acetylation. This modification triggered TACC2 degradation via the ubiquitin-proteasome system mediated by the ubiquitin (Ub) E3 ligase subunit, F box L7 (Fbxl7). Our results suggest that TACC2 is destabilized in epithelia by CS-induced KAT2B-mediated acetylation that recruits Fbxl7 contributing to DNA damage, cytotoxicity, and emphysema.
Author Block: T. Nyunoya1, X. Li1, J. Jang2, C. Zou1, R. Mallampalli3; 1Medicine, University of Pittsburgh, Pittsburgh, PA, United States, 2Allegheny Health Network, Pittsburgh, PA, United States, 3PACCM, UPMC Montefiore, Pittsburgh, PA, United States.
Accumulating evidence suggest a causative role for DNA damage and alveolar cell apoptosis in chronic obstructive pulmonary disease (COPD) pathogenesis. However, the molecular basis for cigarette smoke (CS)-induced DNA damage and apoptosis remains to be elucidated. Our recent integrative analysis identified transforming acidic coiled-coil-containing protein 2 (Tacc2) as a COPD candidate gene. Here, we found that smokers with COPD exhibit a marked decrease in lung TACC2 protein levels as compared with smokers without COPD. CS triggered emphysematous changes accompanied by DNA damage in TACC2-/- compared to TACC2+/+ mice. In human bronchial epithelial cells, CS increased binding of TACC2 to the acetyltransferase, KAT2B, thereby increasing TACC2 acetylation. This modification triggered TACC2 degradation via the ubiquitin-proteasome system mediated by the ubiquitin (Ub) E3 ligase subunit, F box L7 (Fbxl7). Our results suggest that TACC2 is destabilized in epithelia by CS-induced KAT2B-mediated acetylation that recruits Fbxl7 contributing to DNA damage, cytotoxicity, and emphysema.
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