Priority Research Papers:
A novel mechanism of regulation of the oncogenic transcription factor GLI3 by toll-like receptor signaling
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Abstract
Stephan J. Matissek1, Mona Karbalivand1, Weiguo Han1, Ava Boutilier1, Estefania Yzar-Garcia1, Laura L. Kehoe1, Devin Storm Gardner1, Adam Hage2, Krista Fleck1, Vicki Jeffers1, Ricardo Rajsbaum2,3 and Sherine F. Elsawa1
1 Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
3 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
Correspondence to:
Sherine F. Elsawa, | email: | [email protected] |
Keywords: GLI3; inflammation; TLR
Received: July 07, 2022 Accepted: July 25, 2022 Published: August 03, 2022
ABSTRACT
The transcription factor GLI3 is a member of the GLI family and has been shown to be regulated by canonical hedgehog (HH) signaling through smoothened (SMO). Little is known about SMO-independent regulation of GLI3. Here, we identify TLR signaling as a novel pathway regulating GLI3 expression. We show that GLI3 expression is induced by LPS/TLR4 in human monocyte cell lines and peripheral blood CD14+ cells. Further analysis identified TRIF, but not MyD88, signaling as the adapter used by TLR4 to regulate GLI3. Using pharmacological and genetic tools, we identified IRF3 as the transcription factor regulating GLI3 downstream of TRIF. Furthermore, 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. We found that IRF3 directly binds to the GLI3 promoter region and this binding was increased upon stimulation of TRIF-IRF3 with Poly(I:C). Furthermore, using Irf3−/− MEFs, we found that Poly(I:C) stimulation no longer induced GLI3 expression. Finally, using macrophages from mice lacking Gli3 expression in myeloid cells (M-Gli3−/−), we found that in the absence of Gli3, LPS stimulated macrophages secrete less CCL2 and TNF-α compared with macrophages from wild-type (WT) mice. Taken together, these results identify a novel TLR-TRIF-IRF3 pathway that regulates the expression of GLI3 that regulates inflammatory cytokines and expands our understanding of the non-canonical signaling pathways involved in the regulation of GLI transcription factors.
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