A mechanism for transcriptional regulation of innate immune response genes by RSV NS1 protein
Biophysical Journal(2023)
Abstract
Human Respiratory syncytial virus (RSV) is a main cause of bronchiolitis in young children and a still unmet target for pediatric vaccines and antiviral drugs. RSV has evolved a unique strategy to evade host immune response by coding for two non-structural proteins NS1 and NS2, identified as interferon antagonists. Recently it was suggested that NS1 modulates host gene transcription via interactions with chromatin and the Mediator complex. Moreover, the C-terminal RSV NS1 α-helix, α3, was reported to be involved in modulation of host response and gene expression. Here, after identifying the MED25 Mediator subunit as an NS1 interactor in a yeast two-hybrid screen, we demonstrated that NS1 directly interacts with MED25 in cells and in vitro. We assigned this interaction to the MED25-ACID domain, a target of viral transcriptional activators, such as Herpes simplex virus VP16. We showed that NS1 α3 primarily targets the VP16 transactivation domain (TAD) binding site of MED25-ACID. In particular, we found out that NS1 could compete with the TAD of ATF6α, a master regulator of ER stress response activated upon viral infection, for MED25-ACID binding. The affinity for MED25-ACID determined using an NS1-α3 peptide was surprisingly low, as compared to that of full-length NS1. Although this can be partly explained by the unfolded state of the isolated peptide, it suggests the presence of a second binding site. We indeed observed that the NS1Δα3 deletion mutant was able to bind to MED25-ACID. Altogether our findings suggest a mechanism for transcription modulation of specific genes by RSV NS1, and hence for modulation of the host immune response, where NS1 competes with cellular TADs for recruitment of the Mediator MED25 subunit.
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Key words
innate immune response genes,immune response,transcriptional regulation
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