Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Mol Cell. 2017 Feb 16;65(4):715-729.e5. doi: 10.1016/j.molcel.2017.01.022.
TRAIL is a potent inducer of apoptosis and has been studied almost exclusively in this context. However, TRAIL can also induce NFκB-dependent expression of multiple pro-inflammatory cytokines and chemokines. Surprisingly, whereas inhibition of caspase activity blocked TRAIL-induced apoptosis, but not cytokine production, knock down or deletion of caspase-8 suppressed both outcomes, suggesting that caspase-8 participates in TRAIL-induced inflammatory signaling in a scaffold role. Consistent with this, introduction of a catalytically inactive caspase-8 mutant into CASP-8 null cells restored TRAIL-induced cytokine production, but not cell death. Furthermore, affinity precipitation of the native TRAIL receptor complex revealed that pro-caspase-8 was required for recruitment of RIPK1, via FADD, to promote NFκB activation and pro-inflammatory cytokine production downstream. Thus, caspase-8 can serve in two distinct roles in response to TRAIL receptor engagement, as a scaffold for assembly of a Caspase-8-FADD-RIPK1 "FADDosome" complex, leading to NFκB-dependent inflammation, or as a protease that promotes apoptosis.
TRAIL 是一种有效的凋亡诱导剂，几乎专门在这种情况下进行研究。然而，TRAIL 也可以诱导 NFκB 依赖性的多种促炎细胞因子和趋化因子的表达。令人惊讶的是，尽管抑制半胱天冬酶活性可以阻断 TRAIL 诱导的凋亡，但不能抑制细胞因子的产生，敲低或缺失 caspase-8 则抑制了这两种结果，表明 caspase-8 以支架的作用参与 TRAIL 诱导的炎症信号转导。与此一致的是，将无催化活性的 caspase-8 突变体引入 CASP-8 缺失细胞中，恢复了 TRAIL 诱导的细胞因子产生，但不引起细胞死亡。此外，天然 TRAIL 受体复合物的亲和沉淀表明，在招募 RIPK1 以促进 NFκB 激活和下游促炎细胞因子产生方面，前半胱天冬酶-8 通过 FADD 是必需的。因此，caspase-8 在响应 TRAIL 受体结合时可以发挥两种不同的作用，作为组装 Caspase-8-FADD-RIPK1“FADDosome”复合物的支架，导致 NFκB 依赖性炎症，或作为促进凋亡的蛋白酶。
