1. IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD
- Author
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Jürgen Behrens, Bea Unterer, Marina Leone, Clara Tenkerian, Felix B. Engel, Heinrich Sticht, Nathalie Britzen-Laurent, Mekala Gunasekaran, Thomas Wittenberg, Elisabeth Naschberger, Veit Wiesmann, Michael Stürzl, and Publica
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Protein domain ,Mutation, Missense ,colorectal cancer ,GTPase ,medicine.disease_cause ,Biochemistry ,Protein Structure, Secondary ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Mediator ,Protein Domains ,GTP-Binding Proteins ,medicine ,Humans ,Molecular Biology ,Transcription factor ,Research Articles ,Mutation ,Cell growth ,Chemistry ,Cell Biology ,Cell biology ,interferons ,030104 developmental biology ,Cytokine ,cell proliferation ,guanylate-binding proteins ,Hippo signaling ,030220 oncology & carcinogenesis ,Research Article ,HeLa Cells ,Transcription Factors - Abstract
Interferon-gamma (IFN-γ) 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-γ-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-γ 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-γ and Hippo pathways. The α9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the α9-helix binds to the DNA-binding domain of the Hippo signaling transcription factor TEA domain protein (TEAD) mediated by the 376VDHLFQK382 sequence at the N-terminus of the GBP-1-α9-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-γ 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 α9-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-γ.
- Published
- 2018