UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes

Abstract

Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER). Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant (H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells are corrected by expression of wild-type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide-sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs.

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

“…1b). Unc93B1, a multiple transmembrane protein, associates with TLR7 or 9 and transports them from the ER to endolysosomes 13,15,21 . Our recent study shows that TLR9 is expressed on the surface of splenic DCs in a Unc93B1-dependent manner 21 .…”

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

“…2a). Unc93B1 transports TLR9 from the ER to endolysosomes 11 . Unc93B1 may also have a role in transporting TLR9 to the cell surface.…”

“…TLR9 is reported to be localized mostly to the endoplasmic reticulum (ER) and transported to endolysosomes upon activation 11,12 . If TLR9 is forced to be expressed on the cell surface, TLR9 signals extracellular self DNA, leading to systemic lethal inflammation 13 .…”

A threshold level of TLR9 mRNA predicts cellular responsiveness to CpG-ODN in haematological and non-haematological tumour cell lines

“…Prior to exposure to microbial DNA, TLR9 is retained within the endoplasmic reticulum [16]. Expression of the functional receptor requires trafficking to endolysosomes, which is facilitated by the chaperone molecule UNC93B1 [17], and requires cleavage of the TLR9 ectodomain [18]. Whilst both fulllength and cleaved forms of TLR9 are able to bind microbial DNA, only the cleaved form is capable of recruiting MyD88 on activation [18], initiating the TLR signalling cascade.…”