IFN- γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD.

IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD.
Biochem J. 2018 Aug 17;:
Authors: Unterer B, Wiesmann V, Gunasekaran M, Sticht H, Tenkerian C, Behrens J, Leone M, Engel FB, Britzen-Laurent N, Naschberger E, Wittenberg T, Stürzl M
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 crosstalk 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 ...

Source: The Biochemical Journal - August 17, 2018 Category: Biochemistry Authors: Unterer B, Wiesmann V, Gunasekaran M, Sticht H, Tenkerian C, Behrens J, Leone M, Engel FB, Britzen-Laurent N, Naschberger E, Wittenberg T, Stürzl M Tags: Biochem J Source Type: research