Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms

Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L720-9. doi: 10.1152/ajplung.00025.2007. Epub 2007 Jun 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Apoptosis*
  • Caspases, Initiator / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytochromes c / metabolism*
  • Cytosol / metabolism
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / pathology
  • Enzyme Activation
  • Humans
  • Inclusion Bodies / metabolism
  • Mitochondria / metabolism
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Folding*
  • Protein Structure, Tertiary
  • Protein Transport
  • Pulmonary Surfactant-Associated Protein C / chemistry*
  • Pulmonary Surfactant-Associated Protein C / metabolism*
  • Regulatory Factor X Transcription Factors
  • Solubility
  • Transcription Factors
  • Ubiquitin / metabolism
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Mutant Proteins
  • Nuclear Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Ubiquitin
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Cytochromes c
  • CASP4 protein, human
  • Caspases, Initiator
  • Proteasome Endopeptidase Complex