Abstract
Mutations in the gene SFTPC, encoding surfactant protein C (SP-C), are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked in a familial, disease-associated SFTPC mutation, L188Q (L184Q [LQ] in mice), into the mouse Sftpc locus. Translation of the mutant proprotein, proSP-CLQ, exceeded that of proSP-CWT in neonatal alveolar type 2 epithelial cells (AT2 cells) and was associated with transient activation of oxidative stress and apoptosis, leading to impaired expansion of AT2 cells during postnatal alveolarization. Differentiation of AT2 to AT1 cells was also inhibited in ex vivo organoid culture of AT2 cells isolated from LQ mice; importantly, treatment with antioxidant promoted alveolar differentiation. Upon completion of alveolarization, SftpcLQ expression was downregulated, leading to resolution of chronic stress responses; however, the failure to restore AT2 cell numbers resulted in a permanent loss of AT2 cells that was linked to decreased regenerative capacity in the adult lung. Collectively, these data support the hypothesis that susceptibility to disease in adult LQ mice is established during postnatal lung development, and they provide a potential explanation for the delayed onset of disease in patients with familial pulmonary fibrosis.
Highlights
Alveolar type 2 epithelial cells (AT2 cells) synthesize and secrete pulmonary surfactant, which is essential for respiration
Constitutive expression of a disease-associated allele encoding a misfolded form of proSP-C (L184Q) resulted in activation of oxidative stress that was linked to a transient increase in Sftpc mRNA translation in neonatal mice
Subsequent induction of multiple cell stress pathways was associated with impaired expansion of AT2 cells during postnatal alveolarization, resulting in a permanent loss of AT2 cells and, decreased regenerative capacity in the adult lung
Summary
Alveolar type 2 epithelial cells (AT2 cells) synthesize and secrete pulmonary surfactant, which is essential for respiration. Surfactant is a complex mixture of lipids and proteins that forms a bioactive film at the alveolar air-liquid interface and reduces surface tension at end expiration. Human SP-C is synthesized as a 197–amino acid integral membrane precursor protein consisting of a cytosolic N-terminal domain (residues 1–23) that directs intracellular trafficking of the proprotein, a hydrophobic membrane–spanning domain that comprises most of the biophysically active, secreted mature peptide (residues 24–58), and a luminal linker region (residues 59–89), followed by the C-terminal BRICHOS domain (residues 90–197). The SP-C proprotein (proSP-C) traverses the secretory pathway from the endoplasmic reticulum (ER) to the multivesicular body (MVB)/late endosome, where Nedd4-2–mediated ubiquitination of a PY motif in the cytosolic domain allows for internalization of proSP-C from the limiting membrane of the MVB to internal vesicles, followed by proteolytic removal of the N- and C-terminal domains to generate the mature SP-C peptide [4, 5]. SFTPC mutations leading to degradation or mistrafficking of proSP-C are linked to pathogenesis in humans
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