A cell biological view of Toll-like receptor function: regulation through compartmentalization

Abstract

An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand-receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.

Figure 1. Toll-like receptor 7 and Toll-like receptor 9 trafficking and processing regulates receptor activation

Toll-like receptor 7 (TLR7) and TLR9 are translated into the endoplasmic reticulum (ER), pass through the Golgi and are sorted to the endolysosomal system. The mechanisms responsible for these sorting steps remain undefined, although UNC93B1 is known to have a role. Following its arrival in the endolysosome, TLR9 (and most likely TLR7) is proteolytically cleaved. This cleavage event generates a functionally competent receptor; as a result, receptor activation is limited to these intracellular subcompartments. Delivery of potential ligands to the TLR7- or TLR9-containing subcompartment seems to be a prerequisite for receptor activation; viruses seem to be delivered efficiently, whereas self nucleic acids are generally excluded. An exception to this paradigm is the delivery of self nucleic acids as part of immune complexes through endocytosis mediated by Fc receptors on dendritic cells and macrophages or directly by immunoglobulins on B cells.

Figure 2. Schematic of the sorting–signalling adaptor paradigm

The Toll/IL-1 receptor (TIR) domain-containing adaptors have one of two roles. MYD88 (myeloid differentiation primary response protein 88) and TRIF (TIR domain-containing adaptor protein inducing IFNβ) function as signalling adaptors that biochemically link Toll-like receptors (TLRs) that are found in several organelles to the downstream kinases that define a given signalling pathway. The recruitment of MYD88 to plasma membrane TLRs and of TRIF to endosomal TLRs depends on the sorting adaptors TIRAP (TIR domain- containing adaptor protein) and TRAM (TRIF-related adaptor molecule). Sorting adaptors do not directly engage downstream kinases but instead directly engage signalling adaptors, promoting their delivery to activated receptors. The recruitment of sorting adaptors to specific subcellular locations is controlled by their intrinsic phosphoinositide-binding activity, which restricts their localization to a subset of organelles that contain TLRs. As such, TIRAP and TRAM can recruit their signalling adaptor partners to a subset of organelles. Whether additional sorting adaptors exist to recruit signalling adaptors to the other subcompartments of the cell is currently unknown. IL-1R, interleukin-1 receptor; LPS, lipopolysaccharide; PtdIns(4,5)P₂, phosphatidylinositol-4,5-bisphospate; TRAF3, TNFR-associated factor 3.