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Chondrodysplasia-inducing COL2A1 p.Gly1170Ser causes an ER storage defect without associated unfolded protein response in chondronoids

ABSTRACT: Chondrodysplasia-inducing COL2A1 p.Gly1170Ser causes an ER storage defect without associated unfolded protein response in chondronoids

PROVIDER: PRJNA1022488 | ENA |

REPOSITORIES: ENA

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Chondrodysplasia-inducing COL2A1 p.Gly1170Ser causes an ER storage defect without associated unfolded protein response in chondronoids

Project description:Collagenopathies are a group of clinically diverse disorders caused by defects in collagen folding and secretion. For example, mutations in the gene encoding collagen type-II (COL2A1), the primary collagen in cartilage, can lead to chondrodysplasias of various severities. One example is the Gly1170Ser substitution in procollagen-II, which causes precocious osteoarthritis and Legg-Calvé-Perthes disease. Here, we develop and characterize a novel induced pluripotent stem cell-based cartilage model of this disease, including both hetero- and homozygous genotypes. Biochemical characterization reveals that Gly1170Ser procollagen-II is notably slow to fold and secrete. Instead, procollagen-II accumulates intracellularly, consistent with an endoplasmic reticulum (ER) storage disorder. Intriguingly, though perhaps due to the pathologic substitution occurring within a triple-helical domain that lacks hydrophobic character, this intra-ER protein accumulation is not recognized by cellular stress responses, such as the unfolded protein response. Interactome studies showed that Gly1170Ser procollagen-II interacts to a greater extent with certain ER chaperones and modifying enzymes, consistent with its slow folding. These findings provide mechanistic elucidation into the etiology of this disease. Moreover, the expandable cartilage model developed here provides a valuable platform to rapidly screen and develop therapeutic strategies that can restore procollagen folding and secretion in this collagenopathy and others.

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Chondrodysplasia-inducing COL2A1 p.Gly1170Ser causes an ER storage defect without associated unfolded protein response in a human cartilage model

Project description:10-plex TMT dataset generated by immunoprecipitation of epitope-tagged COL2A1 constructs along with DSP-crosslinked interactors. This experiment allows for quantitative comparison of wild-type and Gly1170Ser COL2A1 interactomes in HT-1080 cells transiently transfected with COL2A1 under a constitutive promoter. Negative control samples are untransfected HT-1080 cells, used to identify high-confidence collagen-II interactors from non-specific binders.

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ER procollagen storage defect without coupled unfolded protein response drives precocious arthritis.

Project description:Collagenopathies are a group of clinically diverse disorders caused by defects in collagen folding and secretion. For example, mutations in the gene encoding collagen type-II, the primary collagen in cartilage, can lead to diverse chondrodysplasias. One example is the Gly1170Ser substitution in procollagen-II, which causes precocious osteoarthritis. Here, we biochemically and mechanistically characterize an induced pluripotent stem cell-based cartilage model of this disease, including both hetero- and homozygous genotypes. We show that Gly1170Ser procollagen-II is notably slow to fold and secrete. Instead, procollagen-II accumulates intracellularly, consistent with an endoplasmic reticulum (ER) storage disorder. Likely owing to the unique features of the collagen triple helix, this accumulation is not recognized by the unfolded protein response. Gly1170Ser procollagen-II interacts to a greater extent than wild-type with specific ER proteostasis network components, consistent with its slow folding. These findings provide mechanistic elucidation into the etiology of this disease. Moreover, the easily expandable cartilage model will enable rapid testing of therapeutic strategies to restore proteostasis in the collagenopathies.

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