Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

ISGF3 and STAT2/IRF9 Direct Basal and IFN-Induced Transcription through Genome-Wide Binding of Phosphorylated and Unphosphorylated Complexes to Commonly ISRE Containing ISGs

Hanna Nowicka
ORCID logo ,
Agata Sekrecka
,
Katarzyna Blaszczyk
,
Katarzyna Kluzek
,
Chan-Yu Chang
,
Joanna Wesoly
,
Chien-Kuo Lee
,
Hans A. R. Bluyssen
*
Version 1 : Received: 23 October 2023 / Approved: 23 October 2023 / Online: 23 October 2023 (16:24:13 CEST)

A peer-reviewed article of this Preprint also exists.

Nowicka, H.; Sekrecka, A.; Blaszczyk, K.; Kluzek, K.; Chang, C.-Y.; Wesoly, J.; Lee, C.-K.; Bluyssen, H.A.R. ISGF3 and STAT2/IRF9 Control Basal and IFN-Induced Transcription through Genome-Wide Binding of Phosphorylated and Unphosphorylated Complexes to Common ISRE-Containing ISGs. Int. J. Mol. Sci. 2023, 24, 17635. Nowicka, H.; Sekrecka, A.; Blaszczyk, K.; Kluzek, K.; Chang, C.-Y.; Wesoly, J.; Lee, C.-K.; Bluyssen, H.A.R. ISGF3 and STAT2/IRF9 Control Basal and IFN-Induced Transcription through Genome-Wide Binding of Phosphorylated and Unphosphorylated Complexes to Common ISRE-Containing ISGs. Int. J. Mol. Sci. 2023, 24, 17635.

Abstract

To further understand the role of phosphorylation in ISGF3- and STAT2/IRF9-mediated constitutive and long-term IFN-I-stimulated transcriptional responses, we performed RNA-Seq and ChIP-Seq, in combination with phosphorylation inhibition and anti-viral experiments. First, we identified a group of ISRE-containing ISGs that were commonly regulated in IFNα treated WT and STAT1-KO cells. Thus, in 2fTGH and Huh7.5 WT cells IFNα-inducible transcription and anti-viral activity relied on the recruitment of the ISGF3 components STAT1, STAT2 and IRF9 in a phosphorylation- and time-dependent manner. Likewise, in ST2-U3C and Huh-STAT1KO cells lacking STAT1, ISG expression correlated with DNA-binding of phosphorylated STAT2/IRF9. This pointed to a dominant role of classical ISGF3 and STAT2/IRF9, and not U-ISGF3 or U-STAT2/IRF9, in the regulation of early and prolonged ISG expression and viral protection, in WT and STAT1-KO cells. In addition, comparative experiments in U3C (STAT1-KO) cells overexpressing all ISGF3 components (ST1-ST2-IRF9-U3C), revealed a threshold-dependent role of U-ISFG3, and potentially U-STAT2/IRF9, in the regulation of constitutive and possibly long-term IFNα-treated ISG expression and anti-viral activity.

Keywords

Interferon type-I; JAK/STAT signaling; ISGF3; U-ISGF3; STAT2/IRF9; U-STAT2/IRF9; Integrative omics approach; IFN-dependent and -independent transcription

Subject

Biology and Life Sciences, Immunology and Microbiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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