Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C
Résumé
The newly synthesized surfactant protein C precursor (proSP-C) is an integral endoplasmic reticulum (ER) membrane protein with a single metastable polyVal α-helical transmembrane domain that comprises two thirds of the mature peptide. More than 20 mutations in the ER-lumenal, C-terminal domain of proSP-C (CTC), are associated with interstitial lung disease (ILD), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C. Here it is shown that (i) human embryonic kidney cells expressing the ILD associated mutants proSP-CL188Q and proSP-CΔExon4 accumulate Congo red positive amyloid-like inclusions, while cells transfected with the mutant proSP-CI73T do not, (ii) transfection of CTC into cells expressing proSP-CL188Q results in a stable CTC/proSP-CL188Q complex, increased proSP-CL188Q half life and reduced formation of Congo red positive deposits, (iii) replacement of the metastable polyVal transmembrane segment with a stable polyLeu likewise prevents formation of amyloid-like proSP-CL188Q aggregates, and (iv) binding of recombinant CTC to non-helical SP-C blocks SP-C amyloid fibril formation. These data suggest that CTC can prevent the polyVal segment of proSP-C from promoting formation of amyloid-like deposits during biosynthesis, by binding to non-helical conformations. Mutations in the Brichos domain of proSP-C may lead to ILD via loss of CTC chaperone function.
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