Kim Chan-Hee, Paik Donggi, Rus Florentina, Silverman Neal
From the Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
From the Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605
J Biol Chem. 2014 Jul 18;289(29):20092-101. doi: 10.1074/jbc.M113.544841. Epub 2014 Jun 2.
In Drosophila, the Imd pathway is activated by diaminopimelic acid-type peptidoglycan and triggers the humoral innate immune response, including the robust induction of antimicrobial peptide gene expression. Imd and Relish, two essential components of this pathway, are both endoproteolytically cleaved upon immune stimulation. Genetic analyses have shown that these cleavage events are dependent on the caspase-8 like Dredd, suggesting that Imd and Relish are direct substrates of Dredd. Among the seven Drosophila caspases, we find that Dredd uniquely promotes Imd and Relish processing, and purified recombinant Dredd cleaves Imd and Relish in vitro. In addition, interdomain cleavage of Dredd is not required for Imd or Relish processing and is not observed during immune stimulation. Baculovirus p35, a suicide substrate of executioner caspases, is not cleaved by purified Dredd in vitro. Consistent with this biochemistry but contrary to earlier reports, p35 does not interfere with Imd signaling in S2* cells or in vivo.
在果蝇中，Imd信号通路由二氨基庚二酸型肽聚糖激活，并触发体液固有免疫反应，包括强力诱导抗菌肽基因表达。Imd和Relish是该信号通路的两个关键组分，在免疫刺激时二者都会发生内蛋白水解切割。遗传学分析表明，这些切割事件依赖于类半胱天冬酶-8的Dredd，这表明Imd和Relish是Dredd的直接底物。在果蝇的七种半胱天冬酶中，我们发现Dredd独特地促进Imd和Relish的加工，并且纯化的重组Dredd可在体外切割Imd和Relish。此外，Imd或Relish的加工不需要Dredd的结构域间切割，且在免疫刺激过程中未观察到这种切割。杆状病毒p35是执行者半胱天冬酶的自杀底物，在体外不会被纯化的Dredd切割。与这种生物化学特性一致但与早期报道相反，p35不会干扰S2*细胞或体内的Imd信号传导。
