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UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes


Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses1,2,3. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER)4,5,6. 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.

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Figure 1: TLR7 and TLR9 fail to translocate to endolysosomes in 3d cells.
Figure 2: Expression of wild-type UNC93B1 in 3d cells rescues defects of TLR trafficking and signalling.
Figure 3: Wild-type UNC93B1 delivers the nucleotide-sensing TLRs to endolysosomes.
Figure 4: UNC93B1 is dispensable for ligand recognition and signal initiation by TLR.


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We are grateful to J. Vyas for CD63–cherry-expressing lentivirus, B. Beutler for 3d mice, and T. Nishiya for TLR–YFP constructs. We also thank M. Seedorf for sharing his insights on the Ist2p sequence tag and for providing us with Ist2p tag constructs. We thank B. Mueller and J. Loureiro for discussions and critical reading of the manuscript. This study was supported by grants from the NIH (to H.L.P.), the German Research Council (to M.M.B.) and fonds de recherche en sante du Quebec (to M.-E.P.).

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Correspondence to You-Me Kim or Hidde L. Ploegh.

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Kim, YM., Brinkmann, M., Paquet, ME. et al. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452, 234–238 (2008).

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