Nucleic acid-sensing TLRs: trafficking and regulation

Abstract

Toll-like receptors (TLRs) play an important role in innate immune responses against pathogenic microorganisms or tissue damage. Nucleic acid (NA)-sensing TLRs localize in intracellular vesicular compartments and recognize foreign-derived and host-derived nucleic acid ligands. Inappropriate activation of NA-sensing TLRs can cause pathogenic inflammation and autoimmunity. Multiple regulatory mechanisms exist to limit recognition of self-NAs. This review summarizes recent progress that has been made in understanding how NA-sensing TLRs are regulated via trafficking, proteolytic cleavage, as well as ligand processing and recognition.

Figure 1

Self versus non-self discrimination by NA-sensing TLRs and how dysregulated responses can lead to autoimmunity. The intracellular localization of NA-TLRs limits the recognition of self-nucleic acids that are derived from dying cells and primarily found in the extracellular space. DNases continuously degrade free DNA to avoid autoimmune responses. Upon infection, microbial DNA is released into the endolysosome, where it engages with TLRs and triggers a protective immune response. 1) Accumulation of self-nucleic acids due to defective clearance, 2) elevated levels of stabilizing proteins that protect DNA/RNA from degradation, 3) deficient degradation of nucleic acids, 4) as well as increased TLR7 levels can lead to autoimmunity. In some instances, infections can also trigger or exacerbate autoimmunity.

Figure 2

Trafficking pathways regulating the localization of NA-sensing TLRs. Unc93b1 interacts with all NA-sensing TLRs in the ER and facilitates export into COPII vesicles. Unc93b1 remains associated with TLRs after exit from the ER. Individual TLRs may access distinct intracellular compartments and are subject to specific sorting mechanisms. AEP: asparagine endopeptidase; ESCRT: endosomal sorting complexes required for transport; LRO: lysosome-related organelle; PC: proprotein convertase.

Figure 3

Nucleic acid processing and ligand binding by TLRs. Foreign as well as self-derived nucleic acids are delivered to the endolysosome where they are further processed by either DNase II or an unknown RNase to yield shorter fragments that can activate TLRs. TLR9 binds to short single-stranded oligonucleotides with a stimulatory core CpG motif. TLR7/8 recognize nucleoside breakdown products as well as oligoribonucleotides. TLR3 is activated by dsRNA.