Y-Box Binding Protein 1 and RNase UK114 Mediate Monocyte Chemoattractant Protein 1 mRNA Stability in Vascular Smooth Muscle Cells

Abstract

Monocyte chemoattractant protein 1 (MCP-1) plays a pivotal role in many inflammatory processes, including the progression of atherosclerosis and the response of the arterial wall to injury. We previously demonstrated that dexamethasone (Dex) inhibits MCP-1 mRNA accumulation in smooth muscle cells by decreasing its half-life. The effect of Dex was dependent upon the glucocorticoid receptor (GR) and independent of new transcription. Using RNA affinity and column chromatography, we have identified two proteins involved in regulating MCP-1 mRNA stability: Y-box binding protein 1 (YB-1), a multifunctional DNA/RNA-binding protein, and endoribonuclease UK114 (UK). By immunoprecipitation, YB and GR formed a complex present in equal amounts in extracts from untreated and Dex-treated cells. YB-1, UK, and GR small interfering RNA (siRNA) substantially inhibited the effect of Dex on MCP-1 mRNA accumulation. In addition, YB-1 antibody blocked the degradation of MCP-1 mRNA by cytoplasmic extracts from the Dex-treated cells. The degradative activity of extracts immunoprecipitated with antibodies to either YB-1 or GR was blocked with UK antibody. UK did not degrade MCP-1 mRNA; however, upon addition to nondegrading control extracts, it rapidly degraded MCP-1 mRNA. These studies define new roles for GR, YB-1, and UK in the formation of a molecular complex that degrades MCP-1 mRNA.

Interactome analysis reveals versatile functions of Arabidopsis COLD SHOCK DOMAIN PROTEIN 3 in RNA processing within the nucleus and cytoplasm

“…The CSD may serve as an RNA chaperone module in these proteins. YB-1 has been implicated in transcriptional and translational regulation through its ability to interact with other proteins (Kohno et al 2003); however, recent research revealed its novel functions in splicing (Allemand et al 2007) and mRNA degradation (Dhawan et al 2012). Together with our data, it is now clear that CSD proteins are involved in a wide range of cellular processes associated with RNA metabolism and function.…”

Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

“…Previously, YBX1 and the endoribonuclease HRSP12 have been characterized as cellular proteins associated with full-length CCL2 mRNA (Dhawan et al 2012). In the present study, we identified YBX1 as a CCL2 5 ′ UTR-interacting protein.…”

“…Although it has long been appreciated that GR functions as a DNA-binding transcription factor, several recent reports demonstrated the ability of GR to bind a subset of RNAs (Dhawan et al 2007;Kino et al 2010;Ishmael et al 2011;Dhawan et al 2012;Cho et al 2015). Unlike GR binding to DNAs, GR associates with mRNAs even in the absence of a ligand.…”

YB-1 Is an Early and Central Mediator of Bacterial and Sterile Inflammation In Vivo

“…At the transcriptional level, YB-1 regulates the expression of numerous cyto-and chemokines (4)(5)(6) and their receptors (7,8). Because YB-1 is a major component of messenger ribonucleoprotein particles in mammalian cells, it also regulates the stabilization of mRNA and translation of mediators such as TGF-b and CCL2/ MCP-1 (9,10). Furthermore, YB-1 is involved in mRNA processing (11).…”