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

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

doi:10.1172/jci.insight.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.

Highlights

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD), and an accumulating dose over 40 pack-years is a major predictable factor [1]
The mean chord length (CL) of AIR-exposed Tacc2+/+ mice was set to a value of 1.0
Whole lung lysates were obtained from AIR- or cigarette smoke (CS)-exposed Tacc2+/+ and Tacc2–/– mice

Summary

Introduction

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD), and an accumulating dose over 40 pack-years is a major predictable factor [1]. Insights into COPD pathogenesis suggest a role of persistent DNA damage in the pathobiology of COPD [3, 4]. In response to cigarette smoke (CS) exposure, lung cells exhibit an orchestrated signaling process, the DNA damage response (DDR), which senses DNA damage and initiates DNA repair to maintain genomic integrity [5]. The DDR signaling is mediated by phosphoinositide 3-kinase related protein kinases (PIKKs), including ataxia telangiectasia mutated (ATM). ATM, primarily activated by double-strand breaks (DSBs), regulates cell cycle progression and DNA repair through phosphorylating multiple key substrates, including histone H2A at serine 139 (γH2AX). There are 2 major DSB repair pathways, nonhomologous end-joining (NHEJ) and homologous recombination (HR) [6]

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Results

Conclusion