Wang Lai, Du Fenghe, Wang Xiaodong
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Cell. 2008 May 16;133(4):693-703. doi: 10.1016/j.cell.2008.03.036.
The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP.
哺乳动物细胞对肿瘤坏死因子-α（TNF-α）的炎症反应可通过与蛋白质合成抑制剂放线菌酮或Smac模拟物（一种模拟Smac/Diablo蛋白的小分子）共同处理而转变为凋亡。放线菌酮通过消除内源性半胱天冬酶-8抑制剂c-FLIP来促进半胱天冬酶-8的激活，而Smac模拟物则通过触发细胞凋亡抑制蛋白1和2（cIAP1/2）的自降解来实现这一点，导致受体相互作用蛋白激酶（RIPK1）从活化的TNF受体复合物中释放出来，形成一个由RIPK1、FADD和半胱天冬酶-8组成的半胱天冬酶-8激活复合物。这个过程还需要CYLD（一种RIPK1 K63去泛素化酶）的作用。RIPK1对Smac模拟物诱导的半胱天冬酶-8激活至关重要，但对放线菌酮触发的激活则是可有可无的。此外，Smac模拟物诱导的半胱天冬酶-8激活不会被内源性c-FLIP阻断。这些发现表明，TNF-α能够通过两条不同的半胱天冬酶-8激活途径诱导凋亡，这两条途径受到cIAP1/2和c-FLIP的差异调节。
