Isoleucyl-tRNA synthetase 1 novel mutation promotes deposition of pulmonary surfactant through stabilizing Cathepsin Z [RNA-seq]

Isoleucyl-tRNA synthetase 1(IARS1) disorder is a recently identified multi-organ disease, only a limited cases have been reported so far; furthermore, the mechanisms underlying IARS1 mutation and the symptoms remain unknown. In this report, we present four families with seven distinct IARS1 variants, associated with growth retardation, fatty liver, mental development disorder, and severe pulmonary alveolar proteinosis. IARS1-Tyr148Cys/Arg444* mice are established and exhibited pulmonary alveolar proteinosis and other multi-organ disorders that closely mimic human phenotype. Analysis of single cell RNA sequencing of peripheral blood mononuclear cells from patients and lung metabolomics of lung in IARS1-Tyr148Cys/Arg444* mice analysis indicated disruption in phagosome, lysosome and fatty acid metabolism, cholesterol metabolism pathways. IARS1 mutations results in accumulation of surfactant in alveolar macrophages and alveoli in compound heterozygous mouse model, while IARS1 deficiency impairs the post-translation of Cathepsin Z(CTSZ) by inhibiting ubiquitin-mediated degradation. CTSZ depleted also shows abnormal cholesterol degradation and deposition of pulmonary surfactant associated proteins and overexpression CTSZ could rescue IARS1 deficiency related alveolar macrophage disfunction in vitro. These finding suggest that biallelic IARS1 deficiency impair alveolar macrophage, partly by impair CTSZ -dependent degeneration; and IARS1 could consider as a candidate gene in inherit pulmonary alveolar proteinosis.