Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells.
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.
Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Meenakshi
M
Maitra
Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Moushumi
M
Dey
Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Wen-Cheng
WC
Yuan
Center for Pregnancy and Newborn Research, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Peter W
PW
Nathanielsz
Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390. Electronic address: christine.garcia@utsouthwestern.edu.
Christine Kim
CK
Garcia
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000494:pharmacology; D020125:Mutation, Missense; D010215:Papio; D019899:Paracrine Communication / Q000187:drug effects / Q000235:genetics; D010654:Phenylbutyrates / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics / Q000378:metabolism*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D018832:Molecular Chaperones; D010654:Phenylbutyrates; D037662:Pulmonary Surfactant-Associated Protein A; D037721:Pulmonary Surfactant-Associated Protein C; C445842:SFTPA1 protein, human; C489679:SFTPC protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C075773:4-phenylbutyric acid
Genetics; Pulmonary Fibrosis; Pulmonary Surfactant; Transforming Growth Factor Beta (TGFbeta); Unfolded Protein Response