STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1

被引:60
作者
Jiang, Yaping [1 ]
Yu, Min [1 ,2 ]
Hu, Xuena [1 ]
Han, Lu [1 ]
Yang, Kun [1 ]
Ba, Hongping [1 ]
Zhang, Zunyue [1 ]
Yin, Bingjiao [1 ]
Yang, Xiang-Ping [1 ]
Li, Zhuoya [1 ]
Wang, Jing [1 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Basic Med Sch, Dept Immunol, Wuhan 430030, Peoples R China
[2] Third Mil Med Univ, Xinqiao Hosp, Dept Gen Surg, Chongqing, Peoples R China
基金
中国国家自然科学基金;
关键词
TUMOR-NECROSIS-FACTOR; CELL-DEATH; NEUTRAL SPHINGOMYELINASE; FACTOR RECEPTOR; INTERNALIZATION; PATHWAY; GROWTH; SPHINGOSINE-1-PHOSPHATE; INHIBITION; ACTIVATION;
D O I
10.1038/cdd.2016.162
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:660 / 671
页数:12
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