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Mutations in the SFTPC gene lead to misfolding of the encoded protein, surfactant protein C (SP-C). Molecular chaperones play a key role in detecting misfolded SP-C and directing the protein to the proteasome or lysosome for rapid degradation. Failure at any point in this quality-control system can lead to accumulation of cytotoxic protein, type II cell injury and, ultimately, pathogenesis. The goal of this project is to identify the molecular components of this cytoprotective pathway(s) and design reagents that enhance rapid elimination of mutant SP-C in type II epithelial cells.
Dong M, Bridges JP, Apsley K, Xu Y, Weaver TE. ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C. Mol. Biol. Cell. 19:2620-2630. 2008.
Nerelius C, Martin E, Peng S, Gustafsson M, Nordling K, Weaver TE, Johansson J. Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C. Biochem. J. 416:201-209. 2008.
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SP-C proproteinThe N-terminal propeptide (green) and the C-terminal peptide (blue) are cleaved to generate the mature peptide (red) that is secreted into the alveolar airspaces with surfactant lipids. Three disease-associated mutations under study in the Weaver lab are shown: I73T, Δexon 4 (results in deletion of amino acids 109-145) and L188Q.
High expression of the SP-CΔexon4 mutant profoundly disrupts lung development in transgenic mice (TG1). Lower expression of the transgene results in a less severe phenotype (TG2 and TG3). For comparison, a WT lung is shown in the lower right panel.
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