AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10
AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10
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DOI：
10.1038/ncb1650
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发表时间：
2007-11-01
影响因子：
21.3
通讯作者：
Jung, Yong-Keun
中科院分区：
文献类型：
--
作者：
Lee, Ho-June;Pyo, Jong-Ok;Jung, Yong-Keun
线粒体蛋白在细胞凋亡中起重要的调节作用。在这里，我们表明，线粒体腺苷酸激酶2（AK 2）介导的线粒体凋亡，通过形成一个AK 2-FADD-半胱天冬酶-10（AFAC 10）复合物。AK 2的下调减弱了依托泊苷或星形孢菌素诱导的人细胞凋亡，但不是由肿瘤坏死因子相关凋亡诱导配体（TRAIL）或Fas配体（FasL）诱导的凋亡。在内源性凋亡过程中，AK 2易位到细胞质，而这种情况在Apaf-1敲低细胞中减少，并被Bcl-2或Bcl-X-L阻止。向细胞提取物中加入纯化的AK 2蛋白首先通过FADD诱导半胱天冬酶-10活化，随后诱导半胱天冬酶-3活化，但不影响半胱天冬酶-8。在经历内在细胞死亡的细胞中检测到AFAC 10复合物，并且AK 2促进半胱天冬酶-10与FADD的缔合。相反，AFAC 10复合物在几种依托泊苷耐药的人肿瘤细胞系中未检测到。总之，这些结果表明，与FADD和caspase-10协同作用，AK 2介导了一种新的内在凋亡途径，可能参与肿瘤发生。
Mitochondrial proteins function as essential regulators in apoptosis. Here, we show that mitochondrial adenylate kinase 2 ( AK2) mediates mitochondrial apoptosis through the formation of an AK2-FADD-caspase-10 (AFAC10) complex. Downregulation of AK2 attenuates etoposide- or staurosporine-induced apoptosis in human cells, but not that induced by tumour-necrosis-factor-related apoptosis-inducing ligand ( TRAIL) or Fas ligand ( FasL). During intrinsic apoptosis, AK2 translocates to the cytoplasm, whereas this event is diminished in Apaf-1 knockdown cells and prevented by Bcl-2 or Bcl-X-L. Addition of purified AK2 protein to cell extracts first induces activation of caspase-10 via FADD and subsequently caspase-3 activation, but does not affect caspase-8. AFAC10 complexes are detected in cells undergoing intrinsic cell death and AK2 promotes the association of caspase-10 with FADD. In contrast, AFAC10 complexes are not detected in several etoposide-resistant human tumour cell lines. Taken together, these results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis.