Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9
Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9
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DOI：
10.1073/pnas.1200094109
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发表时间：
2012-06-26
影响因子：
11.1
通讯作者：
Mehlen, Patrick
中科院分区：
文献类型：
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作者：
Fombonne, Joanna;Bissey, Pierre-Antoine;Mehlen, Patrick
Patched (Ptc) 是 Sonic Hedghog 的主要受体，是一种肿瘤抑制因子。 Ptc 已被证明是一种依赖性受体，因此在其配体不存在的情况下会引发细胞凋亡。这种细胞凋亡诱导是通过 Ptc 细胞内结构域募集 caspase 激活复合物而发生的，该复合物包括接头蛋白 DRAL 和 TUCAN 以及顶端 caspase-9。我们在这里展示了这种 caspase 激活复合物还包括 E3 泛素连接酶 NEDD4。我们证明 Ptc 介导的细胞凋亡和 Ptc 诱导的 caspase-9 激活需要 NEDD4。我们发现，内在细胞死亡途径的典型诱导剂 Ptc（而不是 Bax）会触发 caspase-9 的多泛素化。此外，无法泛素化的 caspase-9 突变体无法介导 Ptc 诱导的细胞凋亡。总而言之，这些数据支持这样的观点，即 Ptc 依赖性受体通过泛素化特异性地允许 caspase-9 的激活，而泛素化是通过 Ptc 招募 NEDD4 来实现的。
Patched (Ptc), the main receptor for Sonic Hedghog, is a tumor suppressor. Ptc has been shown to be a dependence receptor, and as such triggers apoptosis in the absence of its ligand. This apoptosis induction occurs through the recruitment by the Ptc intracellular domain of a caspase-activating complex, which includes the adaptor proteins DRAL and TUCAN, and the apical caspase-9. We show here that this caspase-activating complex also includes the E3 ubiquitin ligase NEDD4. We demonstrate that Ptc-mediated apoptosis and Ptc-induced caspase-9 activation require NEDD4. We show that Ptc, but not Bax, the prototypical inducer of the intrinsic cell-death pathway, triggers polyubiquitination of caspase-9. Moreover, a caspase-9 mutant that could not be ubiquitinated failed to mediate Ptc-induced apoptosis. Taken together, these data support the view that the Ptc dependence receptor specifically allows the activation of caspase-9 via its ubiquitination, which occurs via the recruitment by Ptc of NEDD4.