Isoleucyl-tRNA synthetase 1 mutation impairs pulmonary surfactant homeostasis by disrupting alveolar macrophage...

Biallelic isoleucyl-tRNA synthetase 1 (IARS1) variants are associated with an IARS1-related phenotype characterized by growth retardation, intellectual disability, muscular hypotonia, infantile hepatopathy, and interstitial lung disease. This rare, early-onset disorder is often lethal. Although several variants have been identified in recent years, their pathogenicity and underlying molecular mechanisms remain poorly understood. In this study, we generated Iars1^Y148C/R444* compound heterozygous mice, which exhibited pulmonary alveolar proteinosis - like lesions, growth retardation, and muscular hypotonia. Lipid metabolomic profiling of these mice revealed dysregulation of cholesterol metabolism pathways. Furthermore, the Iars1 mutation increased surfactant deposition in alveolar macrophages by impairing lysosomal degradation and disrupting lysosome-autophagosome fusion. We also found that partial loss of IARS1 activity interfered with the post-translational processing of cathepsin Z by inhibiting its ubiquitin-mediated degradation. Importantly, exogenous expression of cathepsin Z improved surfactant clearance in macrophages with partial loss of Iars1 activity. Collectively, our findings demonstrate that partial loss of IARS1 activity induces lysosomal dysfunction in alveolar macrophages and promotes pulmonary surfactant accumulation in the alveoli, thereby contributing to the development of pulmonary alveolar proteinosis.