Alveolar Type II Cells from Mice Expressing a Lung Disease‐Associated ABCA3 E292V Mutation Exhibit Alterations in Organellar Homeostasis and Autophagy

The lipid transporter, ATP binding cassette class A3, ABCA3, plays a critical role in the biogenesis of alveolar type II (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with interstitial lung disease (ILD). The most common mutation is a valine for glutamate missense mutation at residue 292 (E292V) which results in a functional impairment of lipid transport in vitro . To characterize the cellular consequences induced by this mutation in vivo , a novel knockin (KI) mouse model carrying allelic ABCA3 E292V mutations was produced. Lung ultrastructure from E292V homozygous mice revealed smaller size but increased numbers of LBs accompanied by increased AT2 cell mitochondrial counts. Examination of 16 wk and 32 wk homozygous E292V mice showed age‐dependent increase in bronchoalveolar lavage cellularity as well as reduction in alveolar wall thickness coupled with enlarged alveolar air spaces. While isolated E292V AT2 cells demonstrated no alterations in the unfolded protein response, an age‐dependent increase in autophagy components LC3‐I/LC3‐II and P62 also developed in these mice. Furthermore, AT2 cell lysates from 32 wk mice showed accompanying increases in the levels of marker antigens for both mitochondria (Tom20) and lysosomes (Lamp1). We conclude that expression of the ABCA3 E292V mutation produces changes in AT2 organellar homeostasis which result in time‐dependent disruption of macroautophagy‐dependent cellular quality control pathways. We speculate that these changes contribute to the phenotype of a vulnerable epithelium susceptible to second hit injuries that promote the pathogenesis of ILD.