The long-term goal of Project 2 is to elucidate the role of ribosomal protein L13a in post-transcriptional regulation of inflammatory gene expression in monocyte/macrophages. Interferon (IFN)-gamma is the classic activator of monocyte/macrophages;it induces rapid transcription of inflammatory growth factors, proteases, chemokines, and generators of radical species. If unregulated, this process becomes chronic and monocyte/macrophage products accumulate, damage host tissue, and contribute to chronic disorders of blood vessels, e.g., atherosclerosis. We have discovered a novel translational control pathway that acts as an endogenous regulator of the inflammatory response. In myeloid cells, IFN-gamma induces assembly of the IFN-Gamma-Activated Inhibitor of Translation (GAIT) complex, which binds an RNA element in the 3?untranslated region of pro-inflammatory target mRNAs, and inhibits their translation. In Preliminary Studies we show that one GAIT protein, L13a, has a critical role in the GAIT system: its function is regulated by phosphorylation, it induces conformational changes in other GAIT proteins to regulate target mRNA recognition, and by interaction with eIF4G it is responsible for the observed translational silencing. Recently, we have shown that stress can alter GAIT system activity and influence inflammatory gene expression. Based on these results, we propose the following hypothesis: IFN-gamma-dependent phosphorylation of L13a induces a conformational change that facilitates its release from the 60S ribosomal subunit, formation of the GAIT complex, and binding to eIF4G to cause translational silencing of inflammatory transcripts;moreover, physiological stress can alter GAIT system function and inflammatory gene expression. We will test this hypothesis by pursuit of three Specific Aims.
In Aim 1 we will determine the mechanism of inducible release of L13a from ribosome in the response to inflammatory stimulus.
In Aim 2 we will determine L13a interactions required for GAIT complex assembly and silencing of inflammatory gene expression.
In Aim 3 we will determine the mechanisms by which stress alters GAIT complex function and inflammatory gene expression.
Our studies will elucidate a new pathway that regulates the synthesis of inflammatory proteins by macrophages, an important process in the development of vascular diseases such as atherosclerosis. The pathway under investigation contributes to the limitation and resolution of chronic inflammation, an important causative factor in disease progression. A deeper understanding of inflammatory stop pathways is important because defects in these pathways can contribute to vascular disorders, and because the pathway itself may present alternative targets for development of novel anti-inflammatory therapeutics.
|Szpak, Dorota; Izem, Lahoucine; Verbovetskiy, Dmitriy et al. (2018) ?M?2 Is Antiatherogenic in Female but Not Male Mice. J Immunol 200:2426-2438|
|Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730|
|Li, Xinmin S; Wang, Zeneng; Cajka, Tomas et al. (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI Insight 3:|
|Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2018) The GAIT translational control system. Wiley Interdiscip Rev RNA 9:|
|Eswarappa, Sandeep M; Potdar, Alka A; Sahoo, Sarthak et al. (2018) Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase. J Biol Chem 293:19148-19156|
|Halawani, Dalia; Gogonea, Valentin; DiDonato, Joseph A et al. (2018) Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains. J Biol Chem 293:8843-8860|
|Brown, J Mark; Hazen, Stanley L (2018) Microbial modulation of cardiovascular disease. Nat Rev Microbiol 16:171-181|
|Hirbawi, Jamila; Bialkowska, Katarzyna; Bledzka, Kamila M et al. (2017) The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation. J Biol Chem 292:14258-14269|
|Plow, Edward F (2017) An enlightening year in vascular biology. Curr Opin Hematol 24:222-223|
|Brown, J Mark; Hazen, Stanley L (2017) Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery. J Biol Chem 292:8560-8568|
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