Endolysosomal processing of toll‐like receptors and their ligands

Innate immune responses occur rapidly after infection, providing some immediate protection and helping to start the slower acting adaptive response. These early responses include recognition by receptor systems, which collectively detect various pathogen‐derived molecular products (PAMPs)—distinct structural entities either not found in the host or not found in particular cell domains [7]. Toll‐like receptors (TLRs) are a key family, and while some TLRs operate at the cell surface, TLRs that detect viral and bacterial nucleic acids (NA), for example, double‐stranded RNA, are found within the lumen of endosomes and lysosomes. TLRs 3,7,8, and 9, which recognize different pathogen‐expressed nucleic acid configurations, fall into this group and are coupled through adaptors to kinase cascades that trigger cytokine production as well as developmental changes in the cell itself (reviewed in [8, 9]). By confining signalling to the endo‐lysosome system, activation should be limited to nucleic acids released following the breakdown of foreign pathogens since self‐DNA and RNA present in the external milieu will be destroyed by DNAse and RNAses. How is the activation of the nucleic‐acid sensing TLRs confined to the endo‐lysosomal pathway? It has been shown that endo‐lysosomal processing of both TLRs, and in some cases, their NA ligands is necessary as is the presence of the chaperone Unc93b1, which guides NA‐sensing TLRs from the ER to the endocytic pathway. A key early finding was that TLR9 underwent a lumenal proteolytic cleavage event and that only cleaved TLR9 engaged the cytosolic signalling adaptor MyD88 [10, 11].

Subsequent studies confirmed and extended the idea that proteolytic processing was required for the activation of TLRs 7,8 and 9. For example, TLR9 and TLR7 signalling in response to their specific agonists required processing by AEP in mouse dendritic and epithelial cells [11, 12]. The absence of AEP or mutation of the AEP cleavage site in the TLR7 lumenal domain blunted the production of inflammatory cytokines [12]. In other cells such as macrophages, cathepsins also contributed to TLR7 as well as TLR3 and 9 processing [13] and in retinal epithelial cells, TLR3 processing depended on cathepsins B and H and was required for signalling [14]. Other studies have demonstrated a role for the pro‐protein convertase furin in processing and activating TLR7 [15] and TLR8 [16] in some human cells. Unlike most endo‐lysosomal proteases, furin is active at neutral pH, and so, TLR7/8 cleavage might occur prior to arrival in the endocytic pathway. Thus, while the principal of TLR processing for foreign NA recognition seems universal, the precise proteases required vary somewhat between species and cell types. Importantly, the cleaved non‐membrane anchored TLR‐fragments remain non‐covalently associated and are still necessary for signalling (reviewed in [17]). Processing appears to be required not for ligand binding but rather for TLR oligomerization [18].

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Large scale ENU mutagenesis screens in the mouse have identified additional players in NA‐driven TLR signalling [19]. As well as uncovering genes that are directly involved such as Unc93b1 [20], which chaperones TLRs 3, 7 and 9 from the ER to endosomes [20], this strategy and study of natural mouse mutants has also identified genes that are required for general endo/lysosomal integrity and trafficking, such as the AP3 adaptor and the amino acid and oligopeptide carrier SLC15a4, which is critical for TLR7 and 9 driven type‐I interferon (IFN‐I) production in plasmacytoid DCs and B cells [21, 22, 23]. Loss of SLC15a4 disturbed normal endo‐lysosomal v‐ATPase integrity and as a result pH regulation [24]. Kobayashi et al. provided evidence that this also impacted lysosomal mTORC1 signalling and disrupted the IFNAR‐mTOR‐IRF7 circuit that further boosts IFN production [24].

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In the absence of DNAse II, undigested DNA activates cytosolic DNA sensors but not the endosomal sensor TLR9. It turns out that extended dsDNA such as bacterial DNA requires processing, by lysosomal DNAse II, to a 11‐12mer for TLR9 recognition [25]. The structures of TLR7/8 reveal binding sites for guanosine and oligoribonucleotides, indicating that lysosomal RNA degradation products rather than ssRNA itself activate this TLR. Indeed, two endo‐lysosomal RNases, RNase T2 and RNase A were required for TLR8 recognition of its RNA agonists [26]. Thus, lysosomal processing of both NA‐sensing TLRs and NAs themselves is required.

TLR4 can be activated by bacterial lipopolysaccharide but additionally by glycosaminoglycan fragments derived from extracellular matrix components. These accumulate in the mucopolysaccaridoses (MPS)—a family of lysosomal storage diseases (LSDs) characterised by inflammation and skeletal abnormalities. Simonaro et al. showed that TLR4 is activated under these conditions, in part due to lysosomal mislocalization, resulting in elevated serum TNFα levels. In a mouse model of MPS, the ablation of TLR4 or anti‐TNF therapy alleviated skeletal abnormalities [27]. These studies and others (reviewed in ref [28]) indicate that LSDs can lead to aberrant innate immune signalling.

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