title: Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C.
abstract: Mutations in the gene encoding SP-C (surfactant protein C; SFTPC) have been linked to interstitial lung disease (ILD) in children and adults. Expression of the index mutation, SP-C(Deltaexon4), in transiently transfected cells and type II cells of transgenic mice resulted in misfolding of the proprotein, activation of endoplasmic reticulum (ER) stress pathways, and cytotoxicity. In this study, we show that stably transfected cells adapted to chronic ER stress imposed by the constitutive expression of SP-C(Deltaexon4) via an NF-kappaB-dependent pathway. However, the infection of cells expressing SP-C(Deltaexon4) with respiratory syncytial virus resulted in significantly enhanced cytotoxicity associated with accumulation of the mutant proprotein, pronounced activation of the unfolded protein response, and cell death. Adaptation to chronic ER stress imposed by misfolded SP-C was associated with increased susceptibility to viral-induced cell death. The wide variability in the age of onset of ILD in patients with SFTPC mutations may be related to environmental insults that ultimately overwhelm the homeostatic cytoprotective response.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Bridges
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Cheng-Lun
authors.initials: CL
authors.lastname: Na
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Weaver
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007976:Leupeptins / Q000494:pharmacology; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000821:virology; D051907:Lysosomal Membrane Proteins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000032:analysis; D010455:Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017510:Protein Folding; D021382:Protein Sorting Signals; D037721:Pulmonary Surfactant-Associated Protein C; D000071701:Regulatory Factor X Transcription Factors; D012136:Respiratory Syncytial Viruses; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D053148:Caspase 3; D020169:Caspases; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007976:Leupeptins; D051907:Lysosomal Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D009842:Oligopeptides; D010455:Peptides; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D021382:Protein Sorting Signals; D037721:Pulmonary Surfactant-Associated Protein C; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C489679:SFTPC protein, human; C118258:SN50 peptide; C073762:lysyl-aspartyl-glutamyl-leucine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde