RNA-Binding Proteins in the Control of LPS-Induced Macrophage Response

Abstract

Innate immune response is triggered by pathogen components, like lipopolysaccharides (LPS) of gram-negative bacteria. LPS initiates Toll-like receptor 4 (TLR4) signaling, which involves mitogen activated protein kinases (MAPK) and nuclear factor kappa B (NFκB) in different pathway branches and ultimately induces inflammatory cytokine and chemokine expression, macrophage migration and phagocytosis. Timely gene transcription and post-transcriptional control of gene expression confer the adequate synthesis of signaling molecules. As trans-acting factors RNA binding proteins (RBPs) contribute significantly to the surveillance of gene expression. RBPs are involved in the regulation of mRNA processing, localization, stability and translation. Thereby they enable rapid cellular responses to inflammatory mediators and facilitate a coordinated systemic immune response. Specific RBP binding to conserved sequence motifs in their target mRNAs is mediated by RNA binding domains, like Zink-finger domains, RNA recognition motifs (RRM), and hnRNP K homology domains (KH), often arranged in modular arrays. In this review, we focus on RBPs Tristetraprolin (TTP), human antigen R (HUR), T-cell intracellular antigen 1 related protein (TIAR), and heterogeneous ribonuclear protein K (hnRNP K) in LPS induced macrophages as primary responding immune cells. We discuss recent experiments employing RNA immunoprecipitation and microarray analysis (RIP-Chip) and newly developed individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP), photoactivatable ribonucleoside-enhanced crosslinking (PAR-iCLIP) and RNA sequencing techniques (RNA-Seq). The global mRNA interaction profile analysis of TTP, HUR, TIAR, and hnRNP K exhibited valuable information about the post-transcriptional control of inflammation related gene expression with a broad impact on intracellular signaling and temporal cytokine expression.

RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease

“…Also, HuR binds the 3'-UTRs of essential transcription factors and critical cytokine mRNAs to induce epithelial-mesenchymal transition in diabetic nephropathy, suggesting it is involved in the regulation of DKD progression. Therefore, both TTP and HuR regulate the onset, development, and termination of inflammatory responses 19 . Imbalance of the TTP/HuR equilibrium has been observed in many diseases, such as skeletal muscle plasticity and cancer 10,17,20 , but its role in DKD remains to be elucidated.…”

LncSSBP1 Functions as a Negative Regulator of IL-6 Through Interaction With hnRNPK in Bronchial Epithelial Cells Infected With Talaromyces marneffei

“…hnRNPK is a component of heterogeneous nuclear ribonucleoprotein complexes (hnRNPs) that interacts with precursor mRNAs and are by far the most important molecular chaperones that mediate the functions of lncRNAs (18)(19)(20)(21). As a component of hnRNPs, hnRNPK is reported to participate in transcription, splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (34,35). Additionally, there is evidence that hnRNPK contributes to the regulation of RNA 3 ′ -end processing.…”

Microbiota-Mediated Immune Regulation in Atherosclerosis

“…The outer cell membrane of the gram-negative bacteria has conserved components of LPS [ 73 ]. LPS can lead to innate immunity activation and the onset of inflammatory reactions [ 74 ]. Usually, plasma endotoxin levels in patients with sepsis are at ~300 pg/mL; high levels of LPS can cause sepsis both in humans and rodents [ 74 , 75 , 76 ].…”

“…LPS can lead to innate immunity activation and the onset of inflammatory reactions [ 74 ]. Usually, plasma endotoxin levels in patients with sepsis are at ~300 pg/mL; high levels of LPS can cause sepsis both in humans and rodents [ 74 , 75 , 76 ]. “Metabolic endotoxemia” happens when there is a low but constant level of LPS in blood circulation which can cause innate immune responses and consistent inflammation in the circulation without signs of significant infection [ 76 ].…”