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

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.

Immune profiling reveals prognostic genes in high-grade serous ovarian cancer

“…Cellular verification demonstrated that GBP1 and ETV7 may act as tumor suppressors in HGSOC, whereas CXCL13 may promote cell proliferation and migration. These findings are consistent with those of previous studies, although the functions of GBP1 and ETV7 in different tumors are controversial [ 21 , 22 , 34 , 35 ]. Moreover, we conducted immunohistochemistry (IHC) experiments to assess the expression of GBP1.…”

Cytokine-Induced Guanylate Binding Protein 1 (GBP1) Release from Human Ovarian Cancer Cells

“…Recent data indicated that the GBP1-mediated anti-proliferative effects on human colorectal cancer cells DLD1 are mediated by a specific amino acid sequence at the N-terminus of the GBP1-α9-helix, which interacts with the DNA-binding domain of the transcription factor TEA Domain protein (TEAD). In this way, GBP1 inhibits TEAD transcriptional activity and down-regulates TEAD-target genes [51]. The role of GBP1 in EOC is controversial.…”

Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

“…Thus, GBP1 has onco-protective effects beyond direct actin remodeling. Other cytoskeletal-independent activities include interactions between the GBP1 C-terminal domain and Hippo signaling transcription factor TEA domain protein that interferes with expression of YAP1–TEA domain protein target genes needed for cellular hyper-proliferation (Unterer et al, 2018). This may provide some basis for the ability of GBP1 to act as a tumor suppressor in colorectal cancers which arise from dysregulated Hippo signaling (Britzen-Laurent et al, 2013; Hong et al, 2016).…”