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Vol. 19, Issue 6, 2620-2630, June 2008

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ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and The University of Cincinnati College of Medicine, Cincinnati, OH 45229

Submitted July 16, 2007; Revised March 27, 2008; Accepted April 2, 2008
Monitoring Editor: Jeffrey Brodsky

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.

Address correspondence to: Timothy E. Weaver (tim.weaver{at}cchmc.org)

Abbreviations used: ATF, activating transcription factor; BiP, immunoglobulin heavy chain binding protein; CFTR, cystic fibrosis transmembrane conductance regulator; DSP, dithiobis (succinimidylpropionate); EDEM, endoplasmic reticulum-degradation enhancing alpha-mannosidase like protein; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; ERdj, endoplasmic reticulum-localized DnaJ homologue; HA, hemagglutinin; HEK, human embryonic kidney; HSP, heat shock protein; IP, immunoprecipitation; MEF, mouse embryonic fibroblast; SEL1L, sel-1 suppressor of lin-12-like; SP-C, surfactant protein C; UPR, unfolded protein response; UPRE, unfolded protein response element; WT, wild type; XBP-1, X-box binding protein 1.

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