一个de novo主导-负的PSMB8突变导致严重的CANDLE/PRAAS由于被阻止的蛋白质酶生物发生
Sophie Wolfgramm1, Sara Alehashemi2, Martin Wendlandt1
1Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
Annals of the rheumatic diseases
|November 18, 2025
概括
一种新的蛋白酶相关自身炎症综合征 (PRAAS) 变体导致全身炎症和肝脏疾病. 阻断特定的应激反应激酶可以通过向蛋白激酶R (PKR) 和一般控制不可抑制的2 (GCN2) 来治疗这种干扰症.
科学领域:
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 蛋白质酶相关的自身炎症综合征 (PRAAS) 是与20S蛋白质酶功能障碍相关的干扰性疾病.
- 在患有自身炎症症状的患者中发现了PSMB8 (p.G209R) 的新发,主导负 (DN) 变体.
研究的目的:
- 描述DN-PSMB8 p.G209R变种患者的病理机制和治疗反应.
- 研究这些患者免疫失调和蛋白质毒性压力的分子基础.
主要方法:
- 评估了DN-PSMB8 p.G209R变种的患者.
- 评估了干扰素生物标志物,蛋白酶体活性和蛋白质毒性应激反应.
- 进行了T细胞的综合转录和蛋白质分析,以分析免疫失调,线粒体功能和I型干扰素 (IFN-I) 信号传递.
主要成果:
- 患者表现出早期发作的全身炎症,泛肠炎,细胞衰竭,感染和波托-鼻状血管性肝病 (PSVD).
- 该PSMB8 p.G209R变体损害了20S蛋白质酶的形成,导致蛋白质聚合,线粒体功能障碍和脂质处理的改变.
- 通过阻断Janus激酶 (JAK) 信号和综合应激响应 (ISR) 激酶 (PKR,GCN2) 的信号,I型干扰素 (IFN-I) 信号被减少.
结论:
- DN-PSMB8 p.G209R变异扩大了PRAAS谱,导致蛋白酶体成熟停止,并将线粒体功能障碍与ISR联系起来.
- 这些发现涉及血管病理中的细胞衰竭,包括PSVD.
- 确定PKR和GCN2是不适应IFN-I反应的关键媒介和潜在的治疗点.
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