ArticleAmerican journal of physiology. Lung cellular and molecular physiology2015
A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy.
Article in American journal of physiology. Lung cellular and molecular physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.
- Systematic review of drug effects in humans and models with surfactant-processing disease.European respiratory review : an official journal of the European Respiratory Society · 2018Pooled it
- Murine models of pulmonary fibrosis: mechanisms, limitations and translational insights.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- Advances in understanding mitophagy's role in lung injury.Chinese journal of traumatology = Zhonghua chuang shang za zhi · 2026Review
- Lung-tropic dual AAV-SP-C and microRNA gene therapy attenuates lung injury in mutant Sftpc mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.bioRxiv : the preprint server for biology · 2026Article
- Divergent pathways of surfactant protein C maturation for disease-associated isoforms.The Journal of biological chemistry · 2026Article
- Divergent Pathways of Surfactant Protein C Maturation for Disease-Associated Isoforms.bioRxiv : the preprint server for biology · 2025Article
- Endogenous gene editing of alveolar organoids reveals that expression of pathogenic variant SFTPC-I73T disrupts endosomal function, epithelial polarity and wound healing.bioRxiv : the preprint server for biology · 2025Article
- Tissue Fibrosis Decoded via Cellular Senescence: Mechanisms, Treatments, and Emerging Technologies.Aging and disease · 2025Review
- Genetic Disorders of Surfactant Metabolism.NeoReviews · 2025Review
- Interstitial lung disease in the newborn.Journal of perinatology : official journal of the California Perinatal Association · 2025Review
- Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.American journal of respiratory and critical care medicine · 2024Review
- Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis.Frontiers in immunology · 2024Article
- The Role of Mitochondrial Dysfunction in Idiopathic Pulmonary Fibrosis: New Perspectives for a Challenging Disease.Biology · 2023Review
- Lung Science Conference highlights 2023: Post-viral lung diseases - from basic immunology to clinical phenotypes and therapy.Breathe (Sheffield, England) · 2023Article
- The world of rare interstitial lung diseases.European respiratory review : an official journal of the European Respiratory Society · 2023Review
- Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis.International journal of molecular sciences · 2023Article
- Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review.International journal of medical sciences · 2023Review
- Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective.Diagnostics (Basel, Switzerland) · 2022Review
- Gene Therapeutics for Surfactant Dysfunction Disorders: Targeting the Alveolar Type 2 Epithelial Cell.Human gene therapy · 2022Review
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-C(I73T) within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-C(WT)) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-C(I73T) was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-C(I73T) exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-C(I73T). By transmission electron microscopy, hSP-C(I73T) cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-C(I73T) cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-C(I73T) cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-C(I73T) induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
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