BioProject

Osteogenesis imperfecta (OI) is most commonly caused by autosomal dominant mutations in genes encoding collagen type-I. More...

Osteogenesis imperfecta (OI) is most commonly caused by autosomal dominant mutations in genes encoding collagen type-I. Here, we test the hypothesis that modulation of the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the lethal osteogenesis imperfecta (OI)-causing G425S a1(I) variant. We show that specific induction of the UPR’s XBP1s transcriptional response enhances G425S a1(I) secretion up to ~300% of basal levels. Notably, the effect is selective – WT a1(I) secretion is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S a1(I). Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S a1(I) patient fibroblasts includes a higher proportion of the mutant a1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions. Overall design: RNA-seq characterizing two cell lines: WT donor or G425S a1(I) primary patient fibroblast cells. These cell lines were transduced with adenovirus encoding XBP1s or GFP (in triplicate). All cells were treated with 200 uM sodium ascorbate for 24 h before harvesting. Less...