High Dose IFN-β Activates GAF to Enhance Expression of ISGF3 Target Genes in MLE12 Epithelial Cells

Kensei Kishimoto; Kensei Kishimoto; Catera L. Wilder; Justin Buchanan; Minh Nguyen; Minh Nguyen; Chidera Okeke; Chidera Okeke; Alexander Hoffmann; Alexander Hoffmann; Quen J. Cheng; Quen J. Cheng

doi:10.3389/fimmu.2021.651254

Frontiers in Immunology (Apr 2021)

High Dose IFN-β Activates GAF to Enhance Expression of ISGF3 Target Genes in MLE12 Epithelial Cells

Kensei Kishimoto,
Kensei Kishimoto,
Catera L. Wilder,
Justin Buchanan,
Minh Nguyen,
Minh Nguyen,
Chidera Okeke,
Chidera Okeke,
Alexander Hoffmann,
Alexander Hoffmann,
Quen J. Cheng,
Quen J. Cheng

Affiliations

Kensei Kishimoto: Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, United States
Kensei Kishimoto: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, United States
Catera L. Wilder: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
Justin Buchanan: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
Minh Nguyen: Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, United States
Minh Nguyen: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
Chidera Okeke: Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, United States
Chidera Okeke: Department of Life and Physical Sciences, Fisk University, Nashville, TN, United States
Alexander Hoffmann: Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, United States
Alexander Hoffmann: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
Quen J. Cheng: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
Quen J. Cheng: Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, United States

DOI: https://doi.org/10.3389/fimmu.2021.651254
Journal volume & issue: Vol. 12

Abstract

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Interferon β (IFN-β) signaling activates the transcription factor complex ISGF3 to induce gene expression programs critical for antiviral defense and host immune responses. It has also been observed that IFN-β activates a second transcription factor complex, γ-activated factor (GAF), but the significance of this coordinated activation is unclear. We report that in murine lung epithelial cells (MLE12) high doses of IFN-β indeed activate both ISGF3 and GAF, which bind to distinct genomic locations defined by their respective DNA sequence motifs. In contrast, low doses of IFN-β preferentially activate ISGF3 but not GAF. Surprisingly, in MLE12 cells GAF binding does not induce nearby gene expression even when strongly bound to the promoter. Yet expression of interferon stimulated genes is enhanced when GAF and ISGF3 are both active compared to ISGF3 alone. We propose that GAF may function as a dose-sensitive amplifier of ISG expression to enhance antiviral immunity and establish pro-inflammatory states.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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