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Abstract：
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.
摘要：
胶原病是一组由胶原折叠和分泌缺陷引起的临床上不同的疾病。例如,编码II型胶原的基因突变，软骨中的主要胶原蛋白，会导致各种软骨发育不良。一个例子是Gly1170Ser取代原胶原-II，导致早熟的骨关节炎。这里,我们在生物化学和机械上描述了这种疾病的诱导多能干细胞软骨模型，包括杂合和纯合基因型。我们显示Gly1170Ser原胶原II折叠和分泌非常缓慢。相反，原胶原-II在细胞内积聚，与内质网（ER）储存障碍一致。可能是由于胶原蛋白三螺旋的独特特征，未折叠的蛋白质反应无法识别这种积累。Gly1170Ser原胶原-II与特定ER蛋白抑制网络组分的相互作用程度大于野生型,与它的缓慢折叠一致。这些发现为这种疾病的病因提供了机理阐明。此外，易于扩张的软骨模型将能够快速测试治疗策略，以恢复胶原病中的蛋白稳定。
