Pathogen-sensing Toll-like receptors (TLRs) must be deployed accurately. Here, Fukui et al. show how finely tuned these receptors are. Tweaking a single amino acid in a TLR-trafficking molecule determined whether the signal was green or red for nucleic acid–sensing TLRs (page 1339).
TLR7 and TLR9 recognize viral nucleic acids—RNA and DNA, respectively—in endolysosomes. By sequestering TLR7 and TLR9 within the ER, unstimulated dendritic cells and B cells avoid misfiring on bits of host DNA and RNA, which are normally degraded before reaching endolysosomes.
A second guard against TLR misfiring is provided by the membrane-spanning ER protein Unc93B1, which delivers TLR7 and TLR9 to endolysosomes only when the cell is properly activated. Without Unc93B1, nucleic acid–sensing TLRs stay in the ER and never send their signals.
Here, Fukui et al. show that Unc93B1 alternately dispatched TLR7 and TLR9 in dendritic cells, depending on whether the unabridged protein or a slightly altered one was expressed. And the TLR7/9 decision came down to a single amino acid. The usual aspartate at position 34 (D34) of Unc93B1 enhanced TLR9 trafficking and inhibited TLR7. Cutting off the N terminus of the protein or swapping the aspartate for alanine favored TLR7 trafficking over TLR9. The authors suspect that TLR7 inhibition requires an as-yet-unknown molecular middleman that binds to Unc93B1 via D34.
Because the more common version of Unc93B1 primarily traffics TLR9, the authors suggest that dendritic cells are biased toward DNA sensing. Both TLR7 and TLR9 lead to the production of type I interferons, known promoters of autoimmunity. By ensuring that only one of these TLRs leaves the ER at a time, Unc93B1 may be indirectly keeping type I interferon expression under control.