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Cigarette smoke exposure enhances transforming acidic coiled-coil–containing protein 2 turnover and thereby promotes emphysema
Rama K. Mallampalli, … , Li Lan, Toru Nyunoya
Rama K. Mallampalli, … , Li Lan, Toru Nyunoya
Published January 30, 2020
Citation Information: JCI Insight. 2020;5(2):e125895. https://doi.org/10.1172/jci.insight.125895.
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Research Article Cell biology Pulmonology

Cigarette smoke exposure enhances transforming acidic coiled-coil–containing protein 2 turnover and thereby promotes emphysema

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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.

Authors

Rama K. Mallampalli, Xiuying Li, Jun-Ho Jang, Tomasz Kaminski, Aki Hoji, Tiffany Coon, Divay Chandra, Starr Welty, Yaqun Teng, John Sembrat, Mauricio Rojas, Yutong Zhao, Robert Lafyatis, Chunbin Zou, Frank Sciurba, Prithu Sundd, Li Lan, Toru Nyunoya

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Figure 1

Smokers with COPD exhibit decreased TACC2 protein.

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Smokers with COPD exhibit decreased TACC2 protein.
(A) The stage of COPD...
(A) The stage of COPD was determined by the Global Initiative for Obstructive Lung Disease (GOLD) criteria (44). Stage 2, moderate; stage 3, severe; and stage 4, very severe. Control represents smokers with normal pulmonary function. Whole lung parenchyma lysates were obtained from a total of 22 smokers with various GOLD stages of COPD. Immunoblot (IB) analysis was performed for TACC2. (B) The densitometry data (TACC2/β-actin) obtained from A are expressed as mean ± SEM. One-way ANOVA with Bonferroni correction was made. *P < 0.05 (control vs. GOLD stage 2); **P < 0.01 (control vs. GOLD stage 3/4). (C) Total RNA was isolated from whole lung parenchymal tissues obtained from the same donors (control and GOLD stages 3 and 4) as in A. Steady-state levels of TACC2 mRNA were measured by RT-PCR. The relative fold difference compared with HPRT1 (control) was expressed. Data are expressed as mean ± SEM. (D) Single cell RNA sequencing was conducted using lung parenchymal tissues obtained from 3 normal human subjects. t-SNE blots were shown. The intensity of purple indicates levels of gene expression. FOXJ1, Forkhead Box J1; SFTPC, Surfactant protein C; EPCAM, Epithelial cell adhesion molecule.

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