A novel mechanism of regulation of the oncogenic transcription factor GLI3 through Toll-like receptor signaling

A new research paper was published in oncotarget on August 3, 2022 entitled “A novel mechanism of regulation of the oncogenic transcription factor GLI3 by Toll-like receptor signaling”.

The transcription factor GLI3 is a member of the GLI family and has been shown to be regulated by the canonical hedgehog signal (HH) through smoothened (SMO). Little is known about the SMO-independent regulation of GLI3.

“Hedgehog (HH) signaling is well known for its role in embryonic development, cancer and inflammation. At the heart of HH signaling are the 2 receptors Patched (PTCH1) and Smoothened (SMO) along with GLI transcription factors. In the absence of HH ligand, PTCH1 inhibits SMO.”

In this study, researchers (Stephan J. Matissek, Mona Karbalivand, Weiguo Han, Ava Boutilier, Estefania Yzar-Garcia, Laura L. Kehoe, Devin Storm Gardner, Adam Hage, Krista Fleck, Vicki Jeffers, Ricardo Rajsbaum, and Sherine F. Elsawa ) from the University of New Hampshire and the University of Texas Medical Branch identified toll-like receptor (TLR) signaling as a novel signaling pathway that regulates GLI3 expression.

Researchers showed that GLI3 expression is induced by LPS/TLR4 in human monocyte cell lines and CD14+ peripheral blood cells. Further analysis identified TRIF but not MyD88 signaling as an adapter used by TLR4 to regulate GLI3. Using pharmacological and genetic tools, they identified IRF3 as the transcription factor that regulates GLI3 downstream of TRIF.

“Furthermore, by using additional TLR ligands that signal through TRIF, such as the TLR4 ligand MPLA and the TLR3 ligand Poly(I:C), we confirm the role of TRIF-IRF3 in the regulation of GLI3.”

They found that IRF3 binds directly to the GLI3 promoter region and that this binding was enhanced upon stimulation of TRIF-IRF3 with poly(I:C). Using Irf3−/− MEFs, researchers found that poly(I:C) stimulation no longer induced GLI3 expression. Finally, using macrophages from mice without Gli3 expression in myeloid cells (M-Gli3−/−), they found that LPS-stimulated macrophages secrete less CCL2 and TNF-α than wild-type (WT) macrophages in the absence of Gli3. mice.

“Taken together, these results identify a novel TLR-TRIF-IRF3 pathway that regulates the expression of GLI3, which regulates inflammatory cytokines, and advances our understanding of non-canonical signaling pathways involved in the regulation of GLI transcription factors.”

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