Biochemistry of Toll‐Like Receptors


Recognition of potentially pathogenic organisms is a critical first step in an immune response. To prevent pathogen outgrowth, this detection must be rapid and initiate a robust inflammatory response. However, inflammation is dangerous, and spurious activation in response to nonthreatening stimuli has the potential to cause autoimmunity and other inflammatory disorders. For this reason, the pattern recognition receptors (PRRs) of the innate immune system have evolved to recognise pathogen‐associated molecular patterns to distinguish between self and potentially infectious nonself. The first discovered and most well‐studied PRRs are the toll‐like receptors (TLRs), which are transmembrane receptors that detect a diverse set of microbe‐specific products. Extensive work has uncovered the proteins required in TLR signalling, but a more complete understanding of the biochemistry of signalling molecules in their cellular context is required to understand the role of TLRs in pathogen detection and clearance.

Key Concepts:

  • Pathogen‐associated molecular patterns are molecular patterns unique to potentially pathogenic microbes, conserved among many species, and essential to the fitness of the microbes that use them.

  • Pattern recognition receptors distinguish self from nonself.

  • Toll‐like receptor ‘sorting adaptors’ define the subcellular location of signal transduction.

  • Toll‐like receptor ‘signalling adaptors’ link the cytosolic TIR domain of the receptor to signalling enzymes.

Keywords: toll‐like receptor; pathogen‐associated molecular pattern; pattern recognition receptor; lipopolysaccharide; innate immunity

Figure 1.

(a) PRRs are positioned at cell membranes and within the cytosol to detect the presence of pathogens. (b) TLRs use sorting adaptors (TIRAP or TRAM) to recruit signalling adaptors (MyD88 or TRIF) to the site of signal transduction. Signalling adaptors bridge the cytosolic TIR domain of the receptor to downstream enzymes. (c) Most TLRs signal through the assembly of the ‘myddsome,’ a multi‐protein complex consisting of TIRAP, MyD88 and IRAKs. (d) Negative regulators such as SOCS1, MyD88s and SARM are cell‐intrinsic negative regulators that target adaptor proteins in TLR signalling. Pathogens such as Brucella and HSV also encode negative regulators of these pathways to evade detection.

Figure 2.

TLRs at the cell surface recognise structural components of bacteria and fungi such as LPS (TLR4), Flagellin (TLR5) or cell wall glycoproteins (TLR2). Endosomal TLRs typically recognise nucleic acid ligands such as unmethylated CpG DNA (TLR9), double or single stranded RNA (TLRs 3 or 7 respectively) or bacterial ribosomal RNA (TLR13).

Figure 3.

(a) The sorting adaptor TIRAP recruits MyD88 to TLRs at the cell surface and within endosomes. TIRAP's lipid binding domain is promiscuous, binding to lipids such as PI(4,5)P2 (at the plasma membrane) and PI(3)P (on early endosomes). (b) TLR4 signals from both the plasma membrane and within endosomes, utilising a difference sorting/signalling adaptor pair in each location. At the cell surface, TIRAP and MyD88 form a myddosome downstream of LPS binding. After undergoing CD14‐dependent endocytosis, TLR4 engages TRAM and TRIF.

Figure 4.

(1) TLRs are synthesised in the ER and loaded into COPII‐coated vesicles, dependent on gp96 and other chaperones. TLRs destined for endosomes (right) require Unc93B1. (2) After glycosylation in the golgi, some TLRs are exported to the cell surface. (3) Upon ligand binding, TLR4 undergoes CD14‐dependent endocytosis. (4) TLR7 translocates directly from the golgi to lysosomes through its interaction with AP‐4. (5) TLR9 is translocated to the cell surface by Unc93B1. At the cell surface, Unc93B1 interacts with AP‐2, which mediates endocytosis and translocation to lysosomes.



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Further Reading

Kagan JC (2012) Defining the subcellular sites of innate immune signal transduction. Trends in Immunology 33(9): 442–448.

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Bonham, Kevin Scott, and Kagan, Jonathan C(Oct 2014) Biochemistry of Toll‐Like Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024234]