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Published 30 January 2006. doi:10.1083/jcb.200508016
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 3, 395-407
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Article

 Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C

James P. Bridges1, Yan Xu1, Cheng-Lun Na1, Hector R. Wong2, and Timothy E. Weaver1

1 Division of Pulmonary Biology and 2 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, OH 45267

Correspondence to Timothy E. Weaver: tim.weaver{at}cchmc.org

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{Delta}exon4, 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{Delta}exon4 via an NF-{kappa}B–dependent pathway. However, the infection of cells expressing SP-C{Delta}exon4 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.

Abbreviations used in this paper: ERAD, ER-associated degradation; ILD, interstitial lung disease; MFI, mean fluorescence intensity; MOI, multiplicity of infection; PI, propidium iodide; RSV, respiratory syncytial virus; SP-C, surfactant protein C; SR, super repressor; UPR, unfolded protein response.


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