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Abstract：
Spondyloepiphyseal dysplasia (SEMD) is a rare disease in which cartilage growth is disrupted, and the DDRGK1 mutation is one of the causative genes. In our study, we established Ddrgk1fl/fl, Col2a1-ERT Cre mice, which showed a thickened hypertrophic zone (HZ) in the growth plate, simulating the previous reported SEMD pathology in vivo. Instead of the classical modulation mechanism towards SOX9, our further mechanism study found that DDRGK1 stabilizes the stress sensor endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) to maintain endoplasmic reticulum (ER) homoeostasis. The loss of DDRGK1 decreased the UFMylation and subsequently led to increased ubiquitylation-mediated IRE1α degradation, causing ER dysfunction and activating the PERK/CHOP/Caspase3 apoptosis pathway. Further DDRGK1 K268R-mutant mice revealed the importance of K268 UFMylation site in IRE1α degradation and subsequent ER dysfunction. In conclusion, DDRGK1 stabilizes IRE1α to ameliorate ER stress and following apoptosis in chondrocytes, which finally promote the normal chondrogenesis.
摘要：
脊椎骨phy发育不良（SEMD）是一种罕见的疾病，其中软骨生长被破坏，DDRGK1突变是致病基因之一。在我们的研究中,我们建立了Ddrgk1fl/fl，Col2a1-ERTCre小鼠，在生长板中显示出增厚的肥大区（HZ），模拟先前报道的体内SEMD病理学。我们的进一步机制研究发现，DDRGK1稳定了应激传感器内质网到核信号1（IRE1α）以维持内质网（ER）的同质性，而不是对SOX9的经典调节机制。DDRGK1的丢失降低了UFMylation，随后导致泛素化介导的IRE1α降解增加，引起ER功能障碍并激活PERK/CHOP/Caspase3凋亡通路。进一步的DDRGK1K268R突变小鼠揭示了K268UFM化位点在IRE1α降解和随后的ER功能障碍中的重要性。总之,DDRGK1稳定IRE1α以改善内质网应激和软骨细胞凋亡，最终促进正常的软骨形成。
