Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-kB Signaling
Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-kB Signaling
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DOI：
10.4049/jimmunol.1203524
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发表时间：
2014-05-01
影响因子：
4.4
通讯作者：
Hofmann, Sigrun R.
中科院分区：
文献类型：
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作者：
Heymann, Michael C.;Winkler, Stefan;Hofmann, Sigrun R.
促炎酶caspase-1在先天免疫系统中发挥重要作用，参与多种炎症。罕见的自然发生的人类caspase-1基因（CASP1）变异导致不同的蛋白质表达和结构以及酶活性降低或缺失。矛盾的是，尽管IL-1 β的产生和分泌减少，但大量具有这种变异的患者仍会出现发热发作。在这项研究中，我们研究了caspase-1变异（原）如何可能导致炎症。在转染模型中，这种变体procaspase-1通过Caspase激活和募集结构域(CARD)/CARD相互作用结合受体相互作用蛋白激酶2 (RIP2)，从而激活NF-kB，而野生型procaspase-1通过酶裂解并释放到上清液中降低细胞内RIP2水平。我们通过共免疫沉淀和共聚焦显微镜研究了蛋白质的相互作用，发现NF-kB的激活被抗RIP2短发夹RNA和RIP2 CARD-only蛋白的表达抑制。总之，变异体procaspase-1结合RIP2，从而激活NF-kB。这一途径可能有助于促炎信号传导。
The proinflammatory enzyme caspase-1 plays an important role in the innate immune system and is involved in a variety of inflammatory conditions. Rare naturally occurring human variants of the caspase-1 gene (CASP1) lead to different protein expression and structure and to decreased or absent enzymatic activity. Paradoxically, a significant number of patients with such variants suffer from febrile episodes despite decreased IL-1 beta production and secretion. In this study, we investigate how variant (pro) caspase-1 can possibly contribute to inflammation. In a transfection model, such variant procaspase-1 binds receptor interacting protein kinase 2 (RIP2) via Caspase activation and recruitment domain (CARD)/CARD interaction and thereby activates NF-kB, whereas wild-type procaspase-1 reduces intracellular RIP2 levels by enzymatic cleavage and release into the supernatant. We approach the protein interactions by coimmunoprecipitation and confocal microscopy and show that NF-kB activation is inhibited by anti-RIP2-short hairpin RNA and by the expression of a RIP2 CARD-only protein. In conclusion, variant procaspase-1 binds RIP2 and thereby activates NF-kB. This pathway could possibly contribute to proinflammatory signaling.