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Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2018-03-05 , DOI: 10.1084/jem.20172222
Dave Boucher 1 , Mercedes Monteleone 1 , Rebecca C. Coll 1 , Kaiwen W. Chen 1 , Connie M. Ross 1 , Jessica L. Teo 1 , Guillermo A. Gomez 1, 2 , Caroline L. Holley 1 , Damien Bierschenk 1 , Katryn J. Stacey 3 , Alpha S. Yap 1 , Jelena S. Bezbradica 1, 4 , Kate Schroder 1
Affiliation  

Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.



中文翻译:

Caspase-1的自我切割是终止炎症小体活性的内在机制

必须严密调节宿主保护性caspase-1的活性以防止病理,但是控制细胞caspase-1活性持续时间的机制尚不清楚。Caspase-1在炎症小体上被激活,这是促进caspase-1二聚化和自动加工的信号平台。先前对重组蛋白的研究确定了由两个p20和两个p10亚基(p20 / p10)组成的caspase-1四聚体为活性物种。在这项研究中,我们报告说,在细胞中,由炎性小体引发的活性caspase-1二聚体的主要种类实际上是全长p46和瞬时种类p33 / p10。进一步的p33 / p10自动加工会以炎症小体的大小和细胞类型指定的动力学发生,这会从炎症小体释放p20 / p10,随后四聚体在细胞中变得不稳定,并且蛋白酶活性终止。因此,炎性体-caspase-1复合物起着全酶的作用,该酶指导caspase-1活性的定位,但同时也具有内在的自我限制机制,可确保caspase-1适时失活。炎性体信号关闭的这种内在机制为炎性体依赖性炎症反应的瞬时性质和协调的时间安排提供了分子基础。

更新日期:2018-03-06
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