Moores UCSD Cancer Center, 3855, Health Sciences Drive, La Jolla, CA 92039-0803, USA.
Apoptosis. 2012 Mar;17(3):229-35. doi: 10.1007/s10495-011-0677-y.
Caspase-8 can trigger cell death following prodomain-mediated recruitment to the 'death-inducing signaling complex.' The prodomain consists of two death effector domain (DED) motifs that undergo homotypic interactions within the cell. Aside from mediating recruitment of procaspase-8, the prodomains have also been implicated in regulating cell survival, proliferation, death, senescence, differentiation, and substrate attachment. Here, we perform the initial characterization of a novel isoform of caspase-8, designated caspase-8 isoform 6 (Casp-8.6), which encodes both prodomain DEDs followed by a unique C-terminal tail. Casp-8.6 is detected in cells of the hematopoietic compartment as well as several other tissues. When Casp-8.6 expression is reconstituted in caspase-8-deficient cells, Casp-8.6 does not significantly impact cellular proliferation, contrasting with our previous results using a domain-defined 'DED-only' construct that lacks the C-terminal tail. Like the DED-only construct, Casp-8.6 also robustly forms 'death effector' filaments, but in contrast to the DED construct, it does not exhibit a dependence upon intact microtubules to scaffold filament formation. Both types of death effector filaments promote apoptosis when expressed in the presence of full length caspase-8 (isoform 1). Together, the results implicate Casp-8.6 as a new physiological modulator of apoptosis.
半胱天冬酶-8（Caspase-8）可通过前导肽介导的募集作用于“死亡诱导信号复合物”，从而引发细胞死亡。前导肽由两个死亡效应结构域（DED）基序组成，在细胞内发生同源相互作用。除了介导procaspase-8 的募集外，前导肽还与细胞存活、增殖、死亡、衰老、分化和底物附着的调节有关。在这里，我们对一种新型的 caspase-8 同工型 Caspase-8 同工型 6（Casp-8.6）进行了初步鉴定，该同工型编码前导肽DED 结构域，其后是独特的 C 末端尾部。Casp-8.6 在造血细胞以及其他几种组织中均有检测到。当 Casp-8.6 在 caspase-8 缺陷型细胞中重新表达时，Casp-8.6 不会显著影响细胞增殖，这与我们之前使用缺乏 C 末端尾部的结构域定义的“DED 仅”构建体的结果形成对比。与 DED 构建体一样，Casp-8.6 也能形成“死亡效应”纤维，但与 DED 构建体不同，它不需要完整的微管来支架纤维形成。当与全长 caspase-8（同工型 1）一起表达时，这两种类型的死亡效应纤维都能促进细胞凋亡。这些结果表明 Casp-8.6 是细胞凋亡的一种新的生理调节剂。
