STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1
STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1
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STAT1通过TNFR1介导跨膜型肿瘤坏死因子-α诱导的死亡诱导信号复合体的形成和细胞凋亡信号
DOI：
10.1038/cdd.2016.162
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发表时间：
2017-04-01
影响因子：
12.4
通讯作者：
Wang, Jing
中科院分区：
文献类型：
--
作者：
Jiang, Yaping;Yu, Min;Wang, Jing
肿瘤坏死因子-α(TNF-α)以两种形式存在：分泌型和跨膜型。虽然两种形式的肿瘤坏死因子-α都能诱导肿瘤细胞的凋亡，但tmTNF-α能够杀伤对sTNF-α介导的细胞毒产生抵抗的肿瘤细胞，这表明它们在信号转导方面的不同。在这里，我们证明了TNFR1的内化对于sTNF-α是至关重要的，但对于tmTNF-α诱导的细胞凋亡来说并不是。STNF-α可诱导肿瘤坏死因子受体1型相关死亡结构域蛋白(Tradd)与TNFR1的死亡结构域(DD)结合，进而激活核因子-kappaB(NF-kappa B)，内化后在细胞质内形成死亡诱导信号复合体(DISC)。相反，tmTNF-α以不依赖DD的方式诱导膜上的视盘形成。它导致信号转导和转录激活因子1(STAT1)与TNFR1的319-337氨基酸区域结合，并诱导STAT1的727位丝氨酸的磷酸化。STAT1的磷酸化促进其与Tradd的结合，从而招募Fas相关蛋白与DD(FADD)和caspase 8形成盘状复合体。这种依赖STAT1的信号会导致细胞凋亡，但不会激活核因子-kappaB。U3A细胞中的STAT1缺乏可以抵消tmTNF-α诱导的椎间盘形成和凋亡。相反，STAT1表达的重建恢复了tmTNF-α诱导的细胞系中的凋亡信号。在体内，tmTNF-α持续抑制含STAT1的HT1080肿瘤的生长，但不抑制含STAT1的U3A肿瘤的生长。我们的数据揭示了未被认识的tmTNF-α诱导细胞凋亡的分子机制，并可能为癌症治疗提供新的线索。
Tumor necrosis factor-alpha (TNF-alpha) exists in two forms: secretory TNF-alpha (sTNF-alpha) and transmembrane TNF-a (tmTNF-alpha). Although both forms of TNF-alpha induce tumor cell apoptosis, tmTNF-alpha is able to kill tumor cells that are resistant to sTNF-alpha-mediated cytotoxicity, indicating their differences in signal transduction. Here, we demonstrate that internalization of TNFR1 is crucial for sTNF-alpha-but not for tmTNF-alpha-induced apoptosis. sTNF-alpha induces binding of tumor necrosis factor receptor type 1-associated death domain protein (TRADD) to the death domain (DD) of TNFR1 and subsequent activation of nuclear factor kappa B (NF-kappa B), and the formation of death-inducing signaling complexes (DISCs) in the cytoplasm after internalization. In contrast, tmTNF-alpha induces DISC formation on the membrane in a DD-independent manner. It leads to the binding of signal transducer and activator of transcription 1 (STAT1) to a region spanning amino acids 319-337 of TNFR1 and induces phosphorylation of serine at 727 of STAT1. The phosphorylation of STAT1 promotes its binding to TRADD, and thus recruits Fas-associated protein with DD (FADD) and caspase 8 to form DISC complexes. This STAT1-dependent signaling results in apoptosis but not NF-kappa B activation. STAT1-deficiency in U3A cells counteracts tmTNF-alpha-induced DISC formation and apoptosis. Conversely, reconstitution of STAT1 expression restores tmTNF-alpha-induced apoptotic signaling in the cell line. Consistently, tmTNF-alpha suppresses the growth of STAT1-containing HT1080 tumors, but not of STAT1-deficient U3A tumors in vivo. Our data reveal an unappreciated molecular mechanism of tmTNF-alpha-induced apoptosis and may provide a new clue for cancer therapy.