Role of COPA Gene Mutation in Lung Epithelial Cells in COPA Syndrome Lung Disease

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Abstract Rationale: COPA syndrome is an autosomal dominant systemic inflammatory disease, which includes interstitial lung disease (ILD) as a major clinical feature. This syndrome is caused by mutations in the COPA gene, leading to dysfunction in the coatomer protein complex I subunit and resulting in immune hyperactivation, such as aberrant activation of the STING pathway. However, the specific role of COPA gene mutations in lung epithelial cells and their contribution to ILD development in COPA syndrome remain unclear. This study aims to elucidate this link.Methods: Single-cell RNA sequencing was performed on explanted lung tissue from a patient with COPA syndrome carrying the COPA E241K mutation. The findings were compared with data from healthy lung and idiopathic pulmonary fibrosis (IPF) samples. Additionally, conditional transgenic mouse models were developed to induce Cre-mediated cell-type-specific conditional overexpression of either wild-type COPA (COPA-WT) or mutant COPA (COPA-MUT). Lung tissue morphology over time was analyzed, as well as sensitivity to bleomycin-induced fibrosis in these mice. To further investigate the cellular effects of COPA mutations, COPA-MUT was overexpressed in HEK293T cells via lentiviral transduction, and gene expression profiles were assessed.Results: Single-cell analysis of lung tissue from the COPA syndrome patient revealed a lower proportion of alveolar epithelial cells compared to healthy and IPF samples. Type II alveolar epithelial cells exhibited reduced expression of surfactant genes but showed upregulation of markers related to cellular senescence and the unfolded protein response (UPR)/integrated stress response (ISR) pathways, indicating a potential role in fibrosis. Although Shh-Cre COPA-MUT mice did not develop spontaneous fibrosis, they exhibited thickened alveolar walls. Compared to Shh-Cre COPA-WT mice, Shh-Cre COPA-MUT mice had increased mortality and greater fibrosis after bleomycin administration. Furthermore, HEK293T cells overexpressing COPA-MUT displayed upregulated genes associated with the UPR/ISR pathways.Conclusions: The presence of COPA gene mutations in lung epithelial cells may contribute to lung tissue remodeling and the pathogenesis of ILD in COPA syndrome, potentially through mechanisms involving upregulation of the UPR/ISR pathways.

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