Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells
Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells
复制标题
细胞因子信号传导抑制剂通过下调白血病 T 细胞中 NF-κB 和线粒体 Bfl-1 促进 Fas 诱导的细胞凋亡
作者：
Jiyoung Oh;Seol;Sinae Ahn;Choong
细胞因子信号转导抑制因子（SOCS）是细胞因子和生长因子诱导的信号转导的负调节因子。最近，它们已成为多功能蛋白质，在炎症，自身免疫和癌症中具有调节作用。我们最近报道SOCS 1通过诱导硫氧还蛋白（thioredoxin）保护蛋白酪氨酸磷酸酶（Protein tyrosine phosphatases）并减弱Jaks而对TNF-α和过氧化氢诱导的T细胞凋亡具有抗凋亡作用。在这项研究中，我们报告，SOCS，相反，促进死亡受体Fas介导的T细胞凋亡。SOCS 1的促凋亡作用表现为Fas诱导的caspase-8活化增加、Bid产生缩短和线粒体功能障碍。caspase-8抑制剂c-Flip和线粒体抗凋亡因子Bfl-1均被SOCS 1显著降低。这些促凋亡反应与Jak或p38/Jnk活性的变化无关，但伴有NF-κB和NF-κ B依赖性报告基因表达的下调。事实上，通过泛素化的p65降解在SOCS 1过表达细胞中加速，而在SOCS 1敲低细胞中减弱。在高NF-κB水平下，SOCS 1消融的细胞显示出对Fas诱导的凋亡的抵抗，这在siBfl-1转染后被废除。结果表明，抑制NF-κ B依赖的促生存因子，如Bfl-1和c-Flip，可能是SOCS促进Fas介导的T细胞凋亡的作用机制。SOCS 3具有类似的促凋亡功能。因为SOCS 1和SOCS 3都是在TCR刺激后诱导的，所以SOCS将通过使活化的T细胞对Fas介导的凋亡敏感来维持T细胞稳态，从而在活化诱导的细胞死亡中发挥作用。
Suppressors of cytokine signaling (SOCS) are known as negative regulators of cytokine- and growth factor–induced signal transduction. Recently they have emerged as multifunctional proteins with regulatory roles in inflammation, autoimmunity, and cancer. We have recently reported that SOCS1 has antiapoptotic functions against the TNF-α– and the hydrogen peroxide–induced T cell apoptosis through the induction of thioredoxin, which protects protein tyrosine phosphatases and attenuates Jaks. In this study, we report that SOCS, on the contrary, promote death receptor Fas-mediated T cell apoptosis. The proapoptotic effect of SOCS1 was manifested with increases in Fas-induced caspase-8 activation, truncated Bid production, and mitochondrial dysfunctions. Both caspase-8 inhibitor c-Flip and mitochondrial antiapoptotic factor Bfl-1 were significantly reduced by SOCS1. These proapoptotic responses were not associated with changes in Jak or p38/Jnk activities but were accompanied with downregulation of NF-κB and NF-κB–dependent reporter gene expression. Indeed, p65 degradation via ubiquitination was accelerated in SOCS1 overexpressing cells, whereas it was attenuated in SOCS1 knockdown cells. With high NF-κB levels, the SOCS1-ablated cells displayed resistance against Fas-induced apoptosis, which was abrogated upon siBfl-1 transfection. The results indicate that the suppression of NF-κB–dependent induction of prosurvival factors, such as Bfl-1 and c-Flip, may serve as a mechanism for SOCS action to promote Fas-mediated T cell apoptosis. SOCS3 exhibited a similar proapoptotic function. Because both SOCS1 and SOCS3 are induced upon TCR stimulation, SOCS would play a role in activation-induced cell death by sensitizing activated T cells toward Fas-mediated apoptosis to maintain T cell homeostasis.
DOI：
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发表时间：
2001
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. A. Keifer;D. Guttridge;B. P. Ashburner;A. Baldwin
通讯作者：
J. A. Keifer;D. Guttridge;B. P. Ashburner;A. Baldwin
影响因子：
24.1
作者：
Jian Zhang;Xuemei Xu;Yong Liu
通讯作者：
Jian Zhang;Xuemei Xu;Yong Liu
影响因子：
16
作者：
Ryo, A;Suizu, F;Lu, KP
通讯作者：
Lu, KP