Regulation of RNA degradation pathways during the lipopolysaccharide response in Macrophages.

Abstract

The innate immune response to LPS is highly dynamic yet tightly regulated. The majority of studies of gene expression have focussed on transcription. However, it is also important to understand how post-transcriptional pathways are regulated in response to inflammatory stimuli as the rate of RNA degradation relative to new transcription is important for overall expression. RNA decay pathways include nonsense-mediated decay, the RNA decay exosome, P-body localized deadenylation, decapping and degradation, and AU-rich element targeted decay mediated by tristetraprolin. Here, bone marrow-derived Mϕs were treated with LPS over a time course of 0, 2, 6, and 24h and the transcriptional profiles were analyzed by RNA sequencing. The data show that components of RNA degradation pathways are regulated during an LPS response. Processing body associated decapping enzyme DCP2 and regulatory subunit DCP1A, and 5' exonuclease XRN1 and sequence specific RNA decay pathways were upregulated. Nonsense mediated decay was also increased in response to LPS induced signaling, initially by increased activation and at later timepoints at the mRNA and protein levels. This leads to increased nonsense mediated decay efficiency across the 24h following LPS treatment. These findings suggest that LPS activation of Mϕs results in targeted regulation of RNA degradation pathways in order to change how subsets of mRNAs are degraded during an inflammatory response.