Cell death is not essential for caspase-1-mediated interleukin-1β activation and secretion
Cell death is not essential for caspase-1-mediated interleukin-1β activation and secretion
复制标题
DOI：
10.1038/cdd.2016.69
复制
发表时间：
2016-11-01
影响因子：
12.4
通讯作者：
Lindqvist, L. M.
中科院分区：
文献类型：
--
作者：
Conos, S. A.;Lawlor, K. E.;Lindqvist, L. M.
半胱天冬酶-1切割并激活促炎细胞因子白细胞介素-1 β（IL-1 β），但IL-1 β释放的机制及其对细胞死亡的依赖性仍然存在争议。为了解决这个问题，我们产生了一种新的炎性小体独立系统，在该系统中，我们通过二聚化直接激活caspase-1。在该系统中，caspase-1二聚化诱导IL-1 β的裂解和分泌，而不需要将caspase-1加工成其p20和p10亚基。此外，直接半胱天冬酶-1二聚化允许半胱天冬酶-1活化IL-1 β与细胞死亡分开。具体来说，我们证明在单细胞水平，IL-1 β可以释放从活的，代谢活跃，细胞后半胱天冬酶-1激活。此外，我们发现，二聚或内源性半胱天冬酶-8也可以直接切割IL-1 β成其生物活性形式，在典型的炎性体成分的情况下。因此，细胞死亡对于生物活性IL-1 β的稳健分泌不是必须的。
Caspase-1 cleaves and activates the pro-inflammatory cytokine interleukin-1 beta ( IL-1 beta), yet the mechanism of IL-1 beta release and its dependence on cell death remains controversial. To address this issue, we generated a novel inflammasome independent system in which we directly activate caspase-1 by dimerization. In this system, caspase-1 dimerization induced the cleavage and secretion of IL-1 beta, which did not require processing of caspase-1 into its p20 and p10 subunits. Moreover, direct caspase-1 dimerization allowed caspase-1 activation of IL-1 beta to be separated from cell death. Specifically, we demonstrate at the single cell level that IL-1 beta can be released from live, metabolically active, cells following caspase-1 activation. In addition, we show that dimerized or endogenous caspase-8 can also directly cleave IL-1 beta into its biologically active form, in the absence of canonical inflammasome components. Therefore, cell death is not obligatory for the robust secretion of bioactive IL-1 beta.