ERdj4 and ERdj5 are required for endoplasmic reticulum-associated protein degradation of misfolded surfactant protein C

Mol Biol Cell. 2008 Jun;19(6):2620-30. doi: 10.1091/mbc.e07-07-0674. Epub 2008 Apr 9.


Mutations in the SFTPC gene associated with interstitial lung disease in human patients result in misfolding, endoplasmic reticulum (ER) retention, and degradation of the encoded surfactant protein C (SP-C) proprotein. In this study, genes specifically induced in response to transient expression of two disease-associated mutations were identified by microarray analyses. Immunoglobulin heavy chain binding protein (BiP) and two heat shock protein 40 family members, endoplasmic reticulum-localized DnaJ homologues ERdj4 and ERdj5, were significantly elevated and exhibited prolonged and specific association with the misfolded proprotein; in contrast, ERdj3 interacted with BiP, but it did not associate with either wild-type or mutant SP-C. Misfolded SP-C, ERdj4, and ERdj5 coprecipitated with p97/VCP indicating that the cochaperones remain associated with the misfolded proprotein until it is dislocated to the cytosol. Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C, but it had little effect on the wild-type protein. Transient expression of ERdj4 and ERdj5 in X-box binding protein 1(-/-) mouse embryonic fibroblasts substantially restored rapid degradation of mutant SP-C proprotein, whereas transfection of HPD mutants failed to rescue SP-C endoplasmic reticulum-associated protein degradation. ERdj4 and ERdj5 promote turnover of misfolded SP-C and this activity is dependent on their ability to stimulate BiP ATPase activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cytosol / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / metabolism*
  • Exons / genetics
  • HSP40 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunoprecipitation
  • Insulin / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Chaperones / metabolism*
  • Mutant Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding
  • Protein Folding*
  • Protein Processing, Post-Translational*
  • Pulmonary Surfactant-Associated Protein C / chemistry*
  • Pulmonary Surfactant-Associated Protein C / metabolism*
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / deficiency
  • Transcription Factors / metabolism
  • Valosin Containing Protein


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • DNAJB9 protein, human
  • DNAJC10 protein, human
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Insulin
  • Membrane Proteins
  • Molecular Chaperones
  • Mutant Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse
  • molecular chaperone GRP78