近日，澳大利亚墨尔本大学John Silke、Najoua Lalaoui与美国国立卫生研究院Daniel L. Kastner、Steven E. Boyden等研究人员合作发现，RIPK1的剪切位点突变可引起自身免疫疾病。该研究成果于2019年12月11日在线发表于国际学术期刊《自然》。

研究人员发现，杂合的错义突变D324N、D324H和D324Y可以阻止人类中RIPK1的半胱天冬酶剪切，并导致早发性周期性发热综合征和严重的间歇性淋巴结病，研究人员将这种情况称为“抗剪切性RIPK1诱导的自体炎症综合征”。

为了定义这种疾病的机制，研究人员产生了抗剪切的Ripk1D325A突变小鼠品系。Ripk1-/-小鼠死于全身性炎症，而Ripk1D325A/D325A小鼠则在胚胎发生过程中死亡。Casp8和Ripk3的联合缺失可以完全防止胚胎致死，但不能单独通过Ripk3或Mlkl的缺失来预防。RIPK1激酶活性的丧失也阻止了Ripk1D325A/D325A胚胎致死性，尽管这些小鼠在断奶之前以依赖RIPK3的方式从多器官炎症中死亡。

一致地，Ripk1D325A/D325A和Ripk1D325A/+细胞对依赖RIPK3的TNF诱导的细胞凋亡和坏死敏感。杂合的Ripk1D325A/+小鼠能够存活并大体正常，但对体内的炎症刺激反应过度。这些结果表明，caspase 介导的RIPK1剪切在胚胎发育过程中的重要性，并表明RIPK1的caspase剪切不仅抑制了坏死，而且在整个生命过程中都参与维持炎症稳态。

据悉，RIPK1是先天性免疫信号通路的关键调节因子。为了确保最佳的炎症反应，RIPK1通过已知的泛素化和磷酸化转录后修饰以及caspase-8介导剪切的来调节。尽管人们认为这种剪切事件会抑制RIPK3的激活与坏死，但其在生理上的相关性仍不清楚。

附：英文原文

Title: Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease

Author: Najoua Lalaoui, Steven E. Boyden, Hirotsugu Oda, Geryl M. Wood, Deborah L. Stone, Diep Chau, Lin Liu, Monique Stoffels, Tobias Kratina, Kate E. Lawlor, Kristien J. M. Zaal, Patrycja M. Hoffmann, Nima Etemadi, Kristy Shield-Artin, Christine Biben, Wanxia Li Tsai, Mary D. Blake, Hye Sun Kuehn, Dan Yang, Holly Anderton, Natasha Silke, Laurens Wachsmuth, Lixin Zheng, Natalia Sampaio Moura, David B. Beck, Gustavo Gutierrez-Cruz, Amanda K. Ombrello, Gineth P. Pinto-Patarroyo, Andrew J. Kueh, Marco J. Herold, Cathrine Hall, Hongying Wang, Jae Jin Chae, Natalia I. Dmitrieva, Mark McKenzie, Amanda Light, Beverly K. Barham, Anne Jones

Issue&Volume: 2019-12-11

Abstract: RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage17. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathya condition we term cleavage-resistant RIPK1-induced autoinflammatory syndrome. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1/ mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.

DOI: 10.1038/s41586-019-1828-5

Source:

https://www.nature.com/articles/s41586-019-1828-5