These rest areas, called DALIS, were previously identified by the group as clumps of ubiquitinated proteins that form transiently in newly activated DCs. Newly made proteins with translational or folding errors, called DRiPs, get ubiquitinated and are a major source of antigenic peptides. But the authors find that an arrest of DRiP processing at DALIS may put this process on hold.
Using an amino acid analogue that causes premature termination to induce and track DRiPs, the authors found that the DALIS are aggregates of DRiPs, which accumulate to high levels upon DC activation. DRiPs are probably targeted to DALIS directly by the translation apparatus, as continuing translation is needed to maintain the aggregates, and translation components are closely associated with DALIS.
The ubiquitination machinery, including the ribosome-associated E3 ubiquitin–ligase CHIP, is also found in DALIS. Ubiquitination normally triggers proteosome cleavage, thus allowing presentation of the resulting fragments. But DALIS somehow delay DRiP degradation for up to 16 h after DC activation. This implies that other DALIS components (as yet unidentified) tag the ubiquitinated DRiPs for temporary survival. The authors speculate that the delay offered by DALIS may favor the presentation of engulfed foreign peptides over the delayed endogenous antigens and thus might limit autoimmune responses. ▪