Endocytic compartments in dendritic cells are unusually leaky, and as a result, a proportion of internalised proteins escape into the cytosol. This leakiness serves to deliver exogenous proteins into the ubiquitin–proteasome degradation system. The presentation of peptides derived from such exogenous proteins on MHC class I molecules is referred to as cross-presentation and is critical for priming CD8⁺ T cells specific to antigens not expressed in dendritic cells (DCs).
We have recently identified the pore-forming protein perforin-2 as a dedicated effector of endocytic escape in cross-presenting DCs. Perforin-2 is among the top 50 most abundant proteins expressed by conventional DC1s. Yet, endocytic compartments in perforin-2-expressing cells maintain their integrity, are capable of acidification, and show no signs of membrane damage.
Perforin-2 is also the only known pore-forming protein with a transmembrane anchor that does not form part of the pore and is cleaved during its maturation. In this talk, I will discuss the cleavage events involved in perforin-2 processing and the role of the transmembrane anchor during pore formation in dendritic cells.