About the Project
Perforin-2 (Mpeg1) is an ancient pore-forming protein of the membrane attack complex perforin/cholesterol-dependent cytolysin (MACPF/CDC) family with essential roles in immunity. Unlike perforin-1, which is secreted by cytotoxic T cells to kill diseased host cells, perforin-2 is expressed in dendritic cells and macrophages, where it is anchored in endosomal and phagosomal membranes. Intriguingly, perforin-2 is reported to perform two distinct functions during immune responses: attacking intravacuolar pathogens and forming pores in endocytic compartments to enable cytosolic delivery of antigens during cross-presentation. The aim of this project is to establish how these two functions are regulated on the molecular level, and whether they involve the formation of pores in two different orientations - away and towards the host membranes. This work will help to establish how one effector can carry out two fundamentally different functions during immune responses.
The project will employ state-of-the-art microscopy techniques (including confocal, live, multispectral, and/or high-resolution approaches) using established as well as novel reagents (e.g. organelle markers delivered by in vitro-transcribed mRNAs, and de novo-designed protein binders). The position is best suited for an enthusiastic student interested in how immune responses are initiated at the molecular level.
References
Laub, M., Chatterjee, R. & Kozik, P. (2026). Anchoring of perforin-2 via the transmembrane domain is required for antigen escape into the cytosol. The EMBO Journal, 1–23. https://doi.org/10.1038/s[contact details available in the full listing]-z
Rodríguez-Silvestre, P., Laub, M., Krawczyk, P. A., Davies, A. K., Schessner, J. P., Parveen, R., Tuck, B. J., McEwan, W. A., Borner, G. H. H. & Kozik, P. (2023). Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells. Science (New York, N.Y.), 380(6651), 1258–1265. https://doi.org/10.1126/science.adg8802
