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Fulltext Phosphorylation of interferon regulatory factor 9 (IRF9)

Paul A, Ismail MN, Tang TH, Ng SK

Mol Biol Rep, 2023 Apr;50(4):3909-3917.
PMID: 36662450 DOI: 10.1007/s11033-023-08253-3

BACKGROUND: IRF9 is a transcription factor that mediates the expression of interferon-stimulated genes (ISGs) through the Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway. The JAK-STAT pathway is regulated through phosphorylation reactions, in which all components of the pathway are known to be phosphorylated except IRF9. The enigma surrounding IRF9 regulation by a phosphorylation event is intriguing. As IRF9 plays a major role in establishing an antiviral state in host cells, the topic of IRF9 regulation warrants deeper investigation.
METHODS: Initially, total lysates of 2fTGH and U2A cells (transfected with recombinant IRF9) were filter-selected and concentrated using phosphoprotein enrichment assay. The phosphoprotein state of IRF9 was further confirmed using Phos-tag™ assay. All protein expression was determined using Western blotting. Tandem mass spectrometry was conducted on immunoprecipitated IRF9 to identify the phosphorylated amino acids. Finally, site-directed mutagenesis was performed and the effects of mutated IRF9 on relevant ISGs (i.e., USP18 and Mx1) was evaluated using qPCR.
RESULTS: IRF9 is phosphorylated at S252 and S253 under IFNβ-induced condition and R242 under non-induced condition. Site-directed mutagenesis of S252 and S253 to either alanine or aspartic acid has a modest effect on the upregulation of USP18 gene-a negative regulator of type I interferon (IFN) response-but not Mx1 gene.
CONCLUSION: Our preliminary study shows that IRF9 is phosphorylated and possibly regulates USP18 gene expression. However, further in vivo studies are needed to determine the significance of IRF9 phosphorylation.

Matched MeSH terms: Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics
Fulltext Interferon Regulatory Factor 9 Structure and Regulation

Paul A, Tang TH, Ng SK

Front Immunol, 2018;9:1831.
PMID: 30147694 DOI: 10.3389/fimmu.2018.01831

Interferon regulatory factor 9 (IRF9) is an integral transcription factor in mediating the type I interferon antiviral response, as part of the interferon-stimulated gene factor 3. However, the role of IRF9 in many important non-communicable diseases has just begun to emerge. The duality of IRF9's role in conferring protection but at the same time exacerbates diseases is certainly puzzling. The regulation of IRF9 during these conditions is not well understood. The high homology of IRF9 DNA-binding domain to other IRFs, as well as the recently resolved IRF9 IRF-associated domain structure can provide the necessary insights for progressive inroads on understanding the regulatory mechanism of IRF9. This review sought to outline the structural basis of IRF9 that guides its regulation and interaction in antiviral immunity and other diseases.

Matched MeSH terms: Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics

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