IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD
Unterer B, Wiesmann V, Gunasekaran M, Sticht H, Tenkerian C, Behrens J, Leone M, Engel F, Britzen-Laurent N, Naschberger E, Wittenberg T, Stürzl M (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 475
Pages Range: 2955-2967
Journal Issue: 18
DOI: 10.1042/BCJ20180123
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.
Authors with CRIS profile
Bea Unterer
Lehrstuhl für Biochemie und Molekulare Medizin
Thomas Wittenberg
Mekala Gunasekaran Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Heinrich Sticht Professur für Bioinformatik Jürgen Behrens Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Felix Engel Department of Nephropathology Nathalie Britzen-Laurent Professur für Molekulare und Experimentelle Chirurgie Elisabeth Naschberger Medizinische Fakultät Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie
Mekala Gunasekaran Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Heinrich Sticht Professur für Bioinformatik Jürgen Behrens Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Felix Engel Department of Nephropathology Nathalie Britzen-Laurent Professur für Molekulare und Experimentelle Chirurgie Elisabeth Naschberger Medizinische Fakultät Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie
Additional Organisation(s)
Involved external institutions
Germany (DE)How to cite
APA:
Unterer, B., Wiesmann, V., Gunasekaran, M., Sticht, H., Tenkerian, C., Behrens, J.,... Stürzl, M. (2018). IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD. Biochemical Journal, 475(18), 2955-2967. https://dx.doi.org/10.1042/BCJ20180123
MLA:
Unterer, Bea, et al. "IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD." Biochemical Journal 475.18 (2018): 2955-2967.
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