Current Knowledge on Procaspase-1 Variants with Reduced or Abrogated Enzymatic Activity in Autoinflammatory Disease
Current Knowledge on Procaspase-1 Variants with Reduced or Abrogated Enzymatic Activity in Autoinflammatory Disease
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DOI：
10.1007/s11926-015-0520-5
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发表时间：
2015-07-01
影响因子：
5
通讯作者：
Roesen-Wolff, Angela
中科院分区：
文献类型：
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作者：
Luksch, Hella;Winkler, Stefan;Roesen-Wolff, Angela
胱天蛋白酶-1是一种促炎酶，在许多炎症性疾病中是必不可少的，包括感染性、自身免疫性和自身炎症性疾病。炎症主要由炎性体的产生介导，炎性体激活半胱天冬酶-1，随后激活白细胞介素（IL）-1 β和IL-18。此外，半胱天冬酶原-1与RIP 2的同型CARD/CARD相互作用，从而激活NF-κ B通路，可能在炎症中发挥一定作用。然而，正常情况下，该途径似乎通过活性（前）胱天蛋白酶-1切割和排泄RIP 2而迅速下调。在不明原因的复发性全身性炎症患者中，检测到CASP 1变体，其通常使caspase-1二聚体界面不稳定。显然，由此产生的酶活性和IL-1 β产生的降低或消除并不能预防发热发作。作为意外的发现，在体外细胞转染模型中，无活性的半胱氨酸天冬氨酸蛋白酶原-1变体通过增加RIP 2介导的NF-κ B活化而显著增强促炎信号传导。一个可能的原因是失活的半胱氨酸天冬氨酸蛋白酶原-1不能切割结合的RIP 2，也不能介导其从细胞内空间排出，从而保持RIP 2-NF-κ B途径上调。因此，促炎作用的酶失活procaspase-1的变体可能部分解释了患者的炎症发作。
Caspase-1 is a proinflammatory enzyme that is essential in many inflammatory conditions including infectious, autoimmune, and autoinflammatory disorders. The inflammation is mainly mediated by the generation of inflammasomes that activate caspase-1 and subsequently interleukin (IL)-1 beta and IL-18. In addition, homotypic CARD/CARD interaction of procaspase-1 with RIP2 and thereby activation of the NF-kappa B pathways may play some role in the inflammation. However, normally, this pathway seems to become down-regulated rapidly by the cleavage and excretion of RIP2 by active (pro-) caspase-1. In patients with unexplained recurrent systemic inflammation, CASP1 variants were detected, which often destabilized the caspase-1 dimer interface. Obviously, the resulting decreased or abrogated enzymatic activity and IL-1 beta production did not prevent the febrile episodes. As an unexpected finding, the inactive procaspase-1 variants significantly enhanced proinflammatory signaling by increasing RIP2 mediated NF-kappa B activation in an in vitro cell transfection model. A likely reason is the failure of inactive procaspase-1 to cleave bound RIP2 and also to mediate its excretion out of the intracelluar space thereby keeping the RIP2-NF-kappa B pathway upregulated. Hence, proinflammatory effects of enzymatically inactive procaspase-1 variants may partially explain the inflammatory episodes of the patients.