Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms |
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Authors: | Mulugeta Surafel Maguire Jean Ann Newitt Jennifer L Russo Scott J Kotorashvili Adam Beers Michael F |
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Affiliation: | Pulmonary, Allergy, and Critical Care Division, Univ. of Pennsylvania School of Medicine, Vernon & Shirley Hill Pavilion, Suite H418, 380 South Univ. Ave., Philadelphia, PA 19104, USA. mulugeta@mail.med.upenn.edu |
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Abstract: | Several mutations within the BRICHOS domain of surfactant protein C (SP-C) have been linked to interstitial lung disease. Recent studies have suggested that these mutations cause misfolding of the proprotein (proSP-C), which initiates the unfolded protein response to resolve improper folding or promote protein degradation. We have reported that in vitro expression of one of these proteins, the exon 4 deletion mutant (hSP-C(Deltaexon4)), causes endoplasmic reticulum (ER) stress, inhibits proteasome function, and activates caspase-3-mediated apoptosis. To further elucidate mechanisms and common pathways for cellular dysfunction, various assays were performed by transiently expressing two SP-C BRICHOS domain mutant (BRISPC) proteins (hSP-C(Deltaexon4), hSP-C(L188Q)) and control proteins in lung epithelium-derived A549 and kidney epithelium-derived (HEK-293) GFP(u)-1 cell lines. Compared with controls, cells expressing either BRICHOS mutant protein consistently exhibited increased formation of insoluble aggregates, enhanced promotion of inositol-requiring enzyme 1-dependent splicing of X-box binding protein-1 (XBP-1), significant inhibition of proteasome activity, enhanced induction of mitochondrial cytochrome c release, and increased activations of caspase-4 and caspase-3, leading to apoptosis. These results suggest common cellular responses, including initiation of cell-death signaling pathways, to these lung disease-associated BRISPC proteins. |
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