期刊
BIOCHEMICAL JOURNAL
卷 475, 期 -, 页码 2955-2967出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20180123
关键词
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资金
- Emerging Fields Initiative (EFI) of the Friedrich Alexander University of Erlangen-Nuremberg
- German Research Foundation (DFG) [KFO 257, SFB 796, FOR 2438, SFB/TRR241, BR 5196/2-1]
- ELAN-Fonds of the University of Erlangen-Nuremberg
- Interdisciplinary Center for Clinical Research (IZKF) of the Clinical Center Erlangen (D28)
- W. Lutz Stiftung
- Forschungsstiftung Medizin am Universitatsklinikum Erlangen
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that exerts important functions in inflammation, infectious diseases, and cancer. The large GTPase human guanylate-binding protein 1 (GBP-1) is among the most strongly IFN-gamma-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-gamma including the inhibition of proliferation, spreading, migration, and invasion and through this exerts anti-tumorigenic activity. However, the mechanisms of GBP-1 anti-tumorigenic activities remain poorly understood. Here, we elucidated the molecular mechanism of the human GBP-1-mediated suppression of proliferation by demonstrating for the first time a cross-talk between the anti-tumorigenic IFN-gamma and Hippo pathways. The alpha 9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the a9-helix binds to the DNA-binding domain of the Hippo signaling transcription factor TEA domain protein (TEAD) mediated by the (376)VDHLFQK(382) sequence at the N-terminus of the GBP-1-alpha 9-helix. Mutation of this sequence resulted in abrogation of both TEAD interaction and suppression of proliferation. Further on, the interaction caused inhibition of TEAD transcriptional activity associated with the down-regulation of TEAD-target genes. In agreement with these results, IFN-gamma treatment of the cells also impaired TEAD activity, and this effect was abrogated by siRNA-mediated inhibition of GBP-1 expression. Altogether, this demonstrated that the alpha 9-helix is the proliferation inhibitory domain of GBP-1, which acts independent of the GTPase activity through the inhibition of the Hippo transcription factor TEAD in mediating the anti-proliferative cell response to IFN-gamma.
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