USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability
USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability
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DOI：
10.1038/onc.2016.215
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发表时间：
2017-01-26
期刊：
影响因子：
8
通讯作者：
Song, J.
中科院分区：
文献类型：
--
作者：
Jeong, M.;Lee, E-W;Song, J.
FLICE样抑制蛋白(FLIP)是死亡受体介导的细胞凋亡的重要调节因子。在这里，我们发现泛素特异肽酶8(USP8)是一种新的脱泛素基翻转异构体(FLIPL)。USP8直接去泛素化和稳定FLIPL，但不是短异构体。USP8缺失导致FLIPL失稳，促进抗Fas、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和肿瘤坏死因子α通过促进死亡诱导信号复合体或TNFR1复合体II的形成而诱导外源性细胞凋亡，从而导致caspase-8和caspase-3的激活。USP8在黑色素瘤和宫颈癌中的表达水平升高，并且USP8和FLIPL的蛋白水平在这些癌细胞系中呈正相关。使用ME-180宫颈癌细胞进行的异种移植分析表明，注射TRAIL后，USP8缺失可减弱肿瘤生长。综上所述，我们的数据表明，USP8是一种新的FLIPL去泛素化酶，通过稳定FLIPL来抑制外源性细胞凋亡。
FLICE-like inhibitory protein (FLIP) is a critical regulator of death receptor-mediated apoptosis. Here, we found ubiquitin-specific peptidase 8 (USP8) to be a novel deubiquitylase of the long isoform of FLIP (FLIPL). USP8 directly deubiquitylates and stabilizes FLIPL, but not the short isoform. USP8 depletion induces FLIPL destabilization, promoting anti-Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha-induced extrinsic apoptosis by facilitating death-inducing signaling complex or TNFR1 complex II formation, which results in the activation of caspase-8 and caspase-3. USP8 mRNA levels are elevated in melanoma and cervical cancers, and the protein levels of USP8 and FLIPL are positively correlated in these cancer cell lines. Xenograft analyses using ME-180 cervical cancer cells showed that USP8 depletion attenuated tumor growth upon TRAIL injection. Taken together, our data indicate that USP8 functions as a novel deubiquitylase of FLIPL and inhibits extrinsic apoptosis by stabilizing FLIPL.