Role of N-Phosphonacetyl-L-Aspartate in Enhancement of Transcription Governed by Interferon-Stimulated Response Elements and Interferon-g-Activated Sites
Abstract
Interferons (IFNs) are cytokines that stimulate the expression of antiviral and proinflammatory genes during infection. IFN-b is a predominant of type I IFN made upon exposure to viruses. IFN-b binds to cell surface receptors and activates the Janus kinase-signal transducer and activator of transcription signaling (JAK-STAT) pathway. STAT1 and STAT2 are phosphorylated and bind to interferon regulatory factor 9 (IRF9) forming the complex known as interferon-stimulated gene factor 3 (ISGF3). ISGF3 is a transcription factor that enhances expression of genes with interferon-stimulated response elements (ISREs). These IFN-stimulated genes (ISGs) play various roles in suppressing viral replication. Recent work from the McDonald lab has demonstrated that treating cells with IFN-b and N-phosphonacetyl-L-aspartate (PALA) enhances expression of STAT1, STAT2, and IRF9. Additionally, there is a significant increase in ISRE-mediated transcription in the presence of IFN-b and PALA when compared to IFN-b alone. Although canonically linked to type II IFN, reports suggest that phosphorylated STAT1 homodimers form in response to type I IFNs as well. This transcription factor regulates expression of genes with IFN-g-activated site (GAS) elements that enhance the killing response in macrophages. The present study aimed to determine if PALA also enhanced GAS-mediated transcription in combination with IFN-b through developing a GAS-GFP reporter cell line.