Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells

Meenakshi Maitra, Moushumi Dey, Wen Cheng Yuan, Peter W. Nathanielsz, Christine Kim Garcia

Research output: Contribution to journalArticle

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Abstract

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

Original languageEnglish (US)
Pages (from-to)27159-27171
Number of pages13
JournalJournal of Biological Chemistry
Volume288
Issue number38
DOIs
StatePublished - Sep 20 2013

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Transforming Growth Factors
Protein C
Surface-Active Agents
Fibrosis
Epithelial Cells
Lung
Unfolded Protein Response
Proteins
Pulmonary Fibrosis
Autocrine Communication
Paracrine Communication
Molecular Chaperones
Missense Mutation
Mutant Proteins
Transducers
Cell death
Carrier Proteins
Cell Death
Cells
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells. / Maitra, Meenakshi; Dey, Moushumi; Yuan, Wen Cheng; Nathanielsz, Peter W.; Garcia, Christine Kim.

In: Journal of Biological Chemistry, Vol. 288, No. 38, 20.09.2013, p. 27159-27171.

Research output: Contribution to journalArticle

Maitra, Meenakshi ; Dey, Moushumi ; Yuan, Wen Cheng ; Nathanielsz, Peter W. ; Garcia, Christine Kim. / Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 38. pp. 27159-27171.
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