Cell Surface Expression of Endosomal Toll-Like Receptors-A Necessity or a Superfluous Duplication?

Abstract

Timely and precise delivery of the endosomal Toll-like receptors (TLRs) to the ligand recognition site is a critical event in mounting an effective antimicrobial immune response, however, the same TLRs should maintain the delicate balance of avoiding recognition of self-nucleic acids. Such sensing is widely known to start from endosomal compartments, but recently enough evidence has accumulated supporting the idea that TLR-mediated signaling pathways originating in the cell membrane may be engaged in various cells due to differential expression and distribution of the endosomal TLRs. Therefore, the presence of endosomal TLRs on the cell surface could benefit the host responses in certain cell types and/or organs. Although not fully understood why, TLR3, TLR7, and TLR9 may occur both in the cell membrane and intracellularly, and it seems that activation of the immune response can be initiated concurrently from these two sites in the cell. Furthermore, various forms of endosomal TLRs may be transported to the cell membrane, indicating that this may be a normal process orchestrated by cysteine proteases-cathepsins. Among the endosomal TLRs, TLR3 belongs to the evolutionary distinct group and engages a different protein adapter in the signaling cascade. The differently glycosylated forms of TLR3 are transported by UNC93B1 to the cell membrane, unlike TLR7, TLR8, and TLR9. The aim of this review is to reconcile various views on the cell surface positioning of endosomal TLRs and add perspective to the implication of such receptor localization on their function, with special attention to TLR3. Cell membrane-localized TLR3, TLR7, and TLR9 may contribute to endosomal TLR-mediated inflammatory signaling pathways. Dissecting this signaling axis may serve to better understand mechanisms influencing endosomal TLR-mediated inflammation, thus determine whether it is a necessity for immune response or simply a circumstantial superfluous duplication, with other consequences on immune response.

Keywords: TLR signaling; TLR3; cell surface expression; innate immune function; nucleic acid-sensing receptors.

Figure 1

Structure of endosomal TLR localized in the endosome/cell membrane, exemplified by TLR3—shown are dimerization site, ECD (ectodomain/extracellular domain), transmembrane helix, and TIR domain (Toll-interleukin-1-receptor domain), as well as functions of the essential elements of the receptor (–28).

Figure 2

Scheme of TLR3 transportation in the cell. The transportation route is initiated in the ER and terminates in the lysosome—site of degradation. TLR3 present on the cell surface may recognize the dsRNA, which is a viral replication intermediate for some viruses, derived from necrotic infected cells. The dsRNA can also be endocytosed and recognized by TLR3 in the endosomes. Pathways requiring further examination are marked with dashed lines.