Mechanisms controlling nucleic acid-sensing Toll-like receptors

Abstract

Nucleic acid (NA)-sensing Toll-like receptors (TLRs) respond to DNA/RNA derived from pathogens and dead cells. Structural studies have revealed a variety of molecular mechanisms by which TLRs sense NAs. Double-stranded RNA and single-stranded DNA directly bind to TLR3 and TLR9, respectively, whereas TLR7 and TLR8 bind to nucleosides and oligoribonucleotides derived from RNAs. Activation of ligand-bound TLRs is influenced by the functional status of TLRs. Proteolytic cleavage of NA-sensing TLRs enables ligand-dependent TLR dimerization. Trafficking of ligand-activated TLRs in endosomal and lysosomal compartments is requisite for production of type I interferons. Activation of NA-sensing TLRs is required for the control of viruses such as herpes simplex virus and endogenous retroviruses. On the other hand, excessive activation of NA-sensing TLRs drives disease progression in a variety of inflammatory diseases including systemic lupus erythematosus, heart failure, arthritis and non-alcoholic steatohepatitis. NA-sensing TLRs are targets for therapeutic intervention in these diseases. We here focus on our recent progresses in our understanding of NA-sensing TLRs.

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

“…Other studies have also pointed out differences in signaling between different TLR7/8 ligands 78 . Human PBMCs respond to R848 and ssRNA with pro-inflammatory cytokines but only ssRNA was able to induce type I IFNs 79 and recent studies suggest ligand-induced trafficking of TLR containing endosomes dictates different responses 22,80,81 .…”

“…Ten functional TLRs have been discovered in humans of which TLR3, TLR7, TLR8, and TLR9 are located in endosomes and lysosomes 17 . TLR7 and TLR8 recognize single-stranded RNA (ssRNA) in the forms of degradation products, nucleosides, and oligoribonucleotides [18][19][20][21][22] while TLR3 and TLR9 bind doublestranded RNA (dsRNA) and double-stranded DNA (dsDNA), respectively 23,24 . Activated TLR dimers recruit adaptor proteins MyD88 (myeloid differentiation primary response 88) or TRIF (Toll/interleukin-1 (IL-1) receptor domain-containing adapter protein inducing interferon-β (IFN-β)) which signal through sequential activation of IRAK (IL-1 receptor-associated kinase) family kinases, IKKs (inhibitor of κB kinase), and MAPKs (mitogen-activated protein kinase), leading to the activation of the transcription factors NF-κB and AP-1-driving inflammatory cytokines, or interferon regulatory factors (IRFs) driving type I IFNs 25 .…”

Endolysosomal compartments as platforms for orchestrating innate immune and metabolic sensors

“…The Innate immune system responds to a variety of pathogens. Recognition of these products depends on pathogen sensors, which include TLRs, NOD‐like receptors (NLRs), and RIG‐I‐like receptors (RLRs) . These pathogen sensors respond to degradation products derived from pathogens.…”

Co‐expression of TLR‐9 and MMP‐13 is associated with the degree of tumour differentiation in prostate cancer

“…Among TLRs, TLR‐9 recognizes unmethylated CpG dinucleotides expressed in bacteria and viruses and also vertebrate DNA. The TLRs are presented in different locations of the cells; for example, TLR‐1, TLR‐2, TLR‐4 and TLR‐5 are represented on the cell membrane surface, while TLR‐9 is intracellular and is located on the endosomal membrane for binding to its ligand . Many studies have shown that TLR‐9 expression is not limited to immune system cells.…”

“…The TLRs are presented in different locations of the cells; for example, TLR-1, TLR-2, TLR-4 and TLR-5 are represented on the cell membrane surface, while TLR-9 is intracellular and is located on the endosomal membrane for binding to its ligand. 12 Many studies have shown that TLR-9 expression is not limited to immune system cells. Expression of TLR-9 was found in various types of normal epithelial cells and also tumour cells such as gastric, brain, lung, and breast.…”