Reporting in Nature Immunology, Bruce Beutler and colleagues have identified an endoplasmic reticulum (ER)-resident protein that is crucial to both Toll-like receptor (TLR) signalling and antigen presentation.

Unlike other TLRs, which are expressed on the cell surface, TLR3, TLR7 and TLR9 are located mainly in endosomes, and they detect nucleic acids. Using the random germline mutagen N-ethyl-N-nitrosourea and by screening for mutants with defective TLR signalling, Beutler and colleagues identified a mutant mouse, denoted triple D (3d), that is defective at detecting nucleic acids but not other TLR ligands. The 3d mutant mice had increased susceptibility to infection with mouse cytomegalovirus, resistance to which is known to require TLR3- and TLR9-signalling pathways. Moreover, the robust interleukin-12 response that is normally induced against a mutant strain of Listeria monocytogenes that cannot escape endosomes was severely impaired in macrophages from 3d mutant mice.

Surprisingly, in addition to these innate sensing defects, mice that were homozygous for the 3d mutation also had impaired MHC class II antigen presentation and defective cross-presentation of exogenous antigen by MHC class I molecules.

The authors localized the 3d mutation to the gene Unc93b1, which encodes a protein of unknown function. Transfection of 3d-mutant-bone-marrow-derived dendritic cells with wild-type Unc93b1 corrected the nucleic-acid-sensing defect and correlated with mouse genotype.

As the endosomal–lysosomal compartment is required by both the TLR-signalling and antigen-presentation pathways that are impaired in 3d-mutant mice, the authors were surprised to observe that UNC93B is expressed mainly in the ER and not in endosomes.

Although further studies are required to identify how UNC93B is involved in these two processes, the authors ruled out a role for UNC93B in endosome acidification and in cellular localization of TLRs and MHC molecules.