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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076491-08
Application #
8374813
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$261,777
Indirect Cost
$89,845
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361
Arif, Abul; Jia, Jie; Halawani, Dalia et al. (2017) Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation. Methods 113:72-82
Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2017) Predicting long-term prognosis in stable peripheral artery disease with baseline functional capacity estimated by the Duke Activity Status Index. Am Heart J 184:17-25
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
Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius et al. (2017) Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol 5:534-543
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2017) The GAIT translational control system. Wiley Interdiscip Rev RNA :
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
Pamir, Nathalie; Hutchins, Patrick M; Ronsein, Graziella E et al. (2017) Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI Insight 2:
Mollenhauer, Martin; Friedrichs, Kai; Lange, Max et al. (2017) Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. Circ Res 121:56-70
Tang, W H Wilson; Wang, Zeneng; Li, Xinmin S et al. (2017) Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem 63:297-306

Showing the most recent 10 out of 262 publications