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首页> 外文期刊>Nature >A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1
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A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1

机译：由RIPK1的不可裂解变异引起的主要自发性炎症

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摘要

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways(1). Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development(2,3). However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomaldominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
机译：RIPK1的激活控制TNF介导的细胞凋亡，坏死性坏死和炎性途径（1）。 caspase-8分别在残基D324和D325之后切割人和小鼠RIPK1，使RIPK1激酶结构域与中间结构域和死亡结构域分离。小鼠RIPK1中的D325A突变导致小鼠发育过程中的胚胎致死性（2,3）。但是，在人类中阻断Caspase-8介导的RIPK1裂解对RIPK1激活的功能重要性尚不清楚。在这里，我们确定了两个带有RIPK1变体的家族（D324V和D324H），它们以常染色体显性方式导致复发性发烧和淋巴结病的明显症状。 caspase-8对RIPK1 D324变体的切割受损，使患者的外周血单核细胞对TNF诱导的RIPK1激活，凋亡和坏死病敏感。与未受影响的对照组相比，这些患者表现出强烈的RIPK1依赖性炎症信号通路激活以及炎性细胞因子和趋化因子的过度产生。此外，我们显示RIPK1突变体D325V或D325H在小鼠胚胎成纤维细胞中的表达不仅赋予对RIPK1激活介导的细胞凋亡和坏死病敏感性增加，而且还诱导了促炎性细胞因子（如IL-6和TNF）。相比之下，患者来源的成纤维细胞显示RIPK1的表达减少，活性氧的产生下调，从而导致对尸体坏死和肥大病的抵抗力。总之，这些数据表明，人类不可裂解的RIPK1变体促进RIPK1的活化，并导致自身炎症性疾病，其特征在于对细胞凋亡和坏死性超敏反应以及外周血单核细胞中炎症反应的增强，以及一种针对多种疾病的补偿机制。成纤维细胞中的促死亡刺激。

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