Macrophages perform a wide range of functions, from defense against pathogens to removal of toxic products of metabolism. As such macrophages are involved in pathogenesis of a large number of infectious, inflammatory and metabolic diseases. The LXR nuclear hormone receptor pathway plays a key role in regulation of macrophage viability. LXR ligands are oxidized lipids and LXR signaling controls the expression of proteins involved in lipid metabolism. In addition LXR controls the expression of molecules involved in inflammation, including CD5L, a macrophage survival factor. We identified TGS1 as a novel regulator of CD5L that is tightly repressed by 3'UTR cis regulatory elements. Significantly, our data show that repression of TGS1 production is relieved in response to LPS, resulting in down-regulation of CD5L. LPS appears to exert its effect by inducing utilization of an upstream alternative Tgs1 polyadenylation site. Our discoveries provide a strong support for TGS1 as a molecule that connects inflammatory and metabolic signaling. We propose to carry out a set of experiments that will 1. Determine the mechanism of post-transcriptional control of Tgs12. Identify regulators of TGS1 post-transcriptional control machinery. By pursuing the proposed aims we will identify trans effectors that act on TGS1 3'UTR cis control elements and characterize TGS1 targets. Moreover we will confirm the role of inducible alternative polyadenylation in regulation of the LXR pathway that controls viability of macrophages. Results of our study will reveal novel details of cross-regulation of metabolic and inflammatory pathways and will therefore have a broad impact on our understanding of pathogenesis of a wide range of diseases
Our study is designed to improve our understanding of how viability of a key immune cell, the macrophage, is controlled under a variety of conditions. We aim to identify specific components of the regulatory machinery that exert this control. Therefore our results will help us define ways to modulate macrophage function in order to manage a wide range of infectious, inflammatory and metabolic diseases.