Post-transcriptional Regulation of Gene Expression in Inflammation
Innate immunity is a highly conserved response that quickly detects and attempts to clear pathogens and harmful environmental stimuli by inducing inflammatory responses. These responses are orchestrated via temporal and highly coordinated regulation of a number of genes. In addition to regulation at the transcriptional level, a majority of these genes are also regulated by post-transcriptional mechanisms that modify mRNA stability and/or translation. The focus of our research is to understand the association between environmental stimuli, post-transcriptional mechanisms of gene expression, and disease pathogenesis. We are specifically interested in:
Investigating how post-transcriptional mechanisms of gene expression regulate the initiation, the progression, and the resolution of inflammation using lung and liver injury models, particularly those caused by environmental toxicants.
We are particularly focussing on Tristetraprolin (TTP) family of RNA binding proteins. This family of proteins has three members including zinc finger protein 36 (ZFP36) or TTP, ZFP36L1, and ZFP36L2. These proteins function by binding to AU-rich elements (AREs) within the 3’untranslated regions (3’UTRs) of certain mRNAs and causing their rapid degradation. In this way, these proteins can regulate a large number of mRNAs at the level of mRNA stability. For instance, the first member, TTP, regulates the stability of a large number of pro-inflammatory mRNAs, and thus, directly regulates the initiation, the progression, and the resolution of inflammation.
Critical domains of Tristetraprolin (TTP): In the center of the figure is a schematic diagram of three critical domains of TTP: The N terminal nuclear export sequence (NES), the central tandem zinc finger domain (TZF domain), and the C terminal NOT1 binding domain (NOT1 BD). At the upper left is shown a structural model of the human TTP TZF domain bound to nine base RNA sequence. At the upper right is a diagram of the crystal structure of the C-terminal NOT1 binding domain peptide of TTP (maroon), binding to the three internal helices from the human NOT1 protein (beige).