title: SFTPC mutations cause SP-C degradation and aggregate formation without increasing ER stress.
abstract: BACKGROUND
  Mutations in the gene encoding surfactant protein C (SP-C) cause familial and sporadic interstitial lung disease (ILD), which is associated with considerable morbidity and mortality. Unfortunately, effective therapeutic options are still lacking due to a very limited understanding of pathomechanisms. Knowledge of mutant SP-C proprotein (proSP-C) trafficking, processing, intracellular degradation and aggregation is a crucial prerequisite for the development of specific therapies to correct aberrant trafficking and processing of proSP-C and to hinder accumulation of cytotoxic aggregates.
  
  
  METHODS
  To identify possible starting points for therapeutic intervention, we stably transfected A549 alveolar epithelial cells with several proSP-C mutations previously found in patients suffering from ILD. Effects of mutant proSP-C were assessed by Western blotting, immunofluorescence and Congo red staining.
  
  
  RESULTS
  A group of mutations (p.I73T, p.L110R, p.A116D and p.L188Q) resulted in aberrant proSP-C products, which were at least partially trafficked to lamellar bodies. Another group of mutations (p.P30L and p.P115L) was arrested in the endoplasmic reticulum (ER). Except for p.I73T, all mutations led to accumulation of intracellular Congo red-positive aggregates. Enhanced ER stress was detectable in none of these stably transfected cells.
  
  
  CONCLUSIONS
  Different SP-C mutations have unique consequences for alveolar epithelial cell biology. As these cannot be predicted based upon the localization of the mutation, our data emphasize the importance of studying individual mutations in detail in order to develop mutation-specific therapies.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Thurm
authors.forename: Eva
authors.initials: E
authors.lastname: Kaltenborn
authors.forename: Sunčana
authors.initials: S
authors.lastname: Kern
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Ralf
authors.initials: R
authors.lastname: Zarbock
mesh_terms: D056809:Alveolar Epithelial Cells; D001343:Autophagy / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human
keywords: A549 cells; ER stress; SFTPC mutations; interstitial lung disease; surfactant protein C