Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

Ramana, Chilakamarti V.

Respiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by Interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Genetic and biochemical studies have shown that transcriptional regulation by IFN-α/β required the formation of Interferon-stimulated gene factor-3 (ISGF-3) complex consisting of Stat1, Stat2, and Irf9 transcription factors. Furthermore, IFN α/β receptor activates multiple signal transduction pathways in parallel to the Jak-Stat pathway and induces several transcription factors at mRNA levels resulting in the secondary and tertiary rounds of transcription. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response-1 (Egr-1) was rapidly induced by IFN-α/β and Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the ISGF-3 complex revealed that IFN-β induction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-β in serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses regulated Egr-1 expression in human lung cell lines. Furthermore, Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients. Rapid induction by interferons, TLR ligands, and respiratory viruses suggests a critical role for Egr-1 in antiviral response and inflammation with potential implications for human health and disease.