Caspase 8 or 10 recruitment to IPS1 complex followed by their dimerization

Induction of inflammatory cytokines in response to poly(I:C) was reduced in caspase -8/10 deficient human embryonic kidney 293(HEK293) cells [Takahashi K et al 2006]. Mammalian caspase-8 and caspase 10 are two large prodomain initiator caspases consisting of two DEDs (death effector domain) through which they interact with the death domain containing adaptors. Caspases-8/10 also contain catalytic domain with highly conserved QACQG motif. Cys residue in the QACQG motif is involved in their catalytic activity.<p> Recruitment of caspases-8 and -10 to the activated receptor complexes is believed to result in procaspase homodimerization and conformational changes, that are followed by proteolytic cleavage [Chen M et al 2002, Boatright KM et al 2003, Keller N et al 2009]. Proteolytic processing of the caspases-8/10 is required to activate NFkB [Shikama Y et al 2003]. In addition, poly(I:C) stimulation induced the processing of caspase-8/10 in HEK293 cells [Takahashi K et al 2006]. The processing is thought to occur by the autocatalytic cross-cleavage [YangX et al 1998, Oberst A et al 2010, Chang DW et al 2003]. Further downstream signaling processes to NFkB activation are mediated by the DED-containing prodomains of caspases-8/10, but do not require their catalytic domain [Shikama Y et al 2003, Chaudhary PM et al 2000, Takahashi K et al 2006]. The detailed mechanism of caspase mediated NFkB activation remains unclear.<p> The formation of heterodimers with caspase's homologue FLIP has been reported to induce NFkB activation [Boatright KM et al 2004, Kataoka T et al 2005, Pop C et al 2011].</p><p> Predicted chicken caspase-8 and caspase-10 proteins show 51 and 44% overall amino acid sequence identity to their human orthologs respectively. Sequence alignment of chicken and human caspases-8 and -10 revealed that the catalytic QACQG motif is conserved in the chicken orthologs. Due to lack of structural data this project does not describe a processing of chicken caspases.

在对多聚（I:C）的应答中，caspase-8/10缺陷型人胚胎肾293（HEK293）细胞中诱导炎症细胞因子的能力降低[Takahashi K 等人，2006]。哺乳动物中的caspase-8和caspase-10是两种由两个DED（死亡效应域）构成的具有大前导结构域的启动caspase，它们通过这些结构域与包含死亡域的适配体相互作用。Caspase-8/10亦含有具有高度保守QACQG基序的催化结构域。QACQG基序中的半胱氨酸残基参与了其催化活性。caspase-8和-10的募集至激活的受体复合物被认为会导致前caspase的同源二聚化和构象变化，随后发生蛋白酶解切割[Chen M 等人，2002；Boatright KM 等人，2003；Keller N 等人，2009]。caspase-8/10的蛋白酶解处理是激活NFkB的必要条件[Shikama Y 等人，2003]。此外，多聚（I:C）的刺激在HEK293细胞中诱导了caspase-8/10的处理[Takahashi K 等人，2006]。这种处理被认为是通过自催化交叉切割[YangX 等人，1998；Oberst A 等人，2010；Chang DW 等人，2003]发生的。进一步下游的信号传导过程至NFkB的激活由caspase-8/10的含有DED的前导结构域介导，但并不需要其催化结构域[Shikama Y 等人，2003；Chaudhary PM 等人，2000；Takahashi K 等人，2006]。caspase介导的NFkB激活的详细机制尚不明确。caspase与其同源物FLIP形成的异源二聚体据报道可诱导NFkB的激活[Boatright KM 等人，2004；Kataoka T 等人，2005；Pop C 等人，2011]。预测的鸡caspase-8和caspase-10蛋白分别与它们的人类同源蛋白具有51%和44%的整体氨基酸序列一致性。鸡和人类caspase-8和-10的序列比对揭示了催化QACQG基序在鸡同源蛋白中得以保守。由于缺乏结构数据，本项目未描述鸡caspase的处理。