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<p>Biallelic isoleucyl-tRNA synthetase 1 (<i>IARS1</i>) variants are associated with an <i>IARS1</i>-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 <i>Iars1</i><sup>Y148C/R444*</sup> 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 <i>Iars1</i> mutation increased surfactant deposition in alveolar macrophages by impairing lysosomal degradation and disrupting lysosome-autophagosome fusion. We also found that partial loss of <i>IARS1</i> 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 <i>Iars1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Weitao Zhou,
  • Dan Dai,
  • Yao Chen,
  • Xiao Han,
  • Xinran Dong,
  • Yunfei Liao,
  • Tong Chen,
  • Huixian Wang,
  • Chen He,
  • Yilei Lu,
  • Chenxin Zheng,
  • Yufeng Zhou,
  • Liling Qian

摘要

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 Iars1Y148C/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.