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

• Published in: Cell death and differentiation Vol. 24; no. 4; pp. 660 - 671
• Main Authors: Jiang, Yaping, Yu, Min, Hu, Xuena, Han, Lu, Yang, Kun, Ba, Hongping, Zhang, Zunyue, Yin, Bingjiao, Yang, Xiang-Ping, Li, Zhuoya, Wang, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 631/250/1933; 631/67/1244; 82/51; 82/79; 82/83; 96/109; 96/2; 96/63; Amino Acid Chloromethyl Ketones - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cadaverine - analogs & derivatives; Cadaverine - pharmacology; Caspase 8 - metabolism; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line; Cytotoxicity; Death Domain Receptor Signaling Adaptor Proteins - metabolism; Fas-Associated Death Domain Protein - antagonists & inhibitors; Fas-Associated Death Domain Protein - genetics; Fas-Associated Death Domain Protein - metabolism; HEK293 Cells; Humans; Immunology; Life Sciences; Mice; NF-kappa B - metabolism; NIH 3T3 Cells; Original Paper; Phosphorylation; Phosphorylation - drug effects; Protein Binding; Proteins; Receptors, Tumor Necrosis Factor, Type I - antagonists & inhibitors; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Signal transduction; Signal Transduction - drug effects; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stem Cells; TNF Receptor-Associated Death Domain Protein - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - toxicity; Tumor necrosis factor-TNF; Tumors; China
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/cdd.2016.162

Tumor necrosis factor-alpha (TNF- α ) exists in two forms: secretory TNF- α (sTNF- α ) and transmembrane TNF- α (tmTNF- α ). Although both forms of TNF- α induce tumor cell apoptosis, tmTNF- α is able to kill tumor cells that are resistant to sTNF- α -mediated cytotoxicity, indicating their differences in signal transduction. Here, we demonstrate that internalization of TNFR1 is crucial for sTNF- α - but not for tmTNF- α -induced apoptosis. sTNF- α 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- κ B), and the formation of death-inducing signaling complexes (DISCs) in the cytoplasm after internalization. In contrast, tmTNF- α 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- κ B activation. STAT1-deficiency in U3A cells counteracts tmTNF- α -induced DISC formation and apoptosis. Conversely, reconstitution of STAT1 expression restores tmTNF- α -induced apoptotic signaling in the cell line. Consistently, tmTNF- α 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- α -induced apoptosis and may provide a new clue for cancer therapy.