Molecular mechanism of the endosomal escape pathway in dendritic cells
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Dendritic cells (DCs) are key players involved in initiation of immune responses against pathogens and cancer. The ability to prime cancer- or pathogen-specific T cells depends on the ability of DCs is to sample antigens from infected or cancer cells and to present them on MHC class I molecules to naïve T cells (a process referred to as cross-presentation). Cross-presentation has been proposed to rely on an unusual cell biological feature of dendritic cells: the ability to import proteins from endosomes and phagosomes into the cytosol, where they can be processed by proteasome into small peptides. This “endolysosomal leakiness” is in striking contrasts to mechanisms present in other cells, where integrity of endosomal and lysosomal membranes is critical for protection of the cells against pathogens, toxins, as well as from the proteolytic content of the lysosomes themselves. We have recently performed CRISPR-Cas9 genetic screen in dendritic cells and identified key players that regulate endosomal escape. We now aim to understand how the proteins identified work together to facilitate membrane leakiness in a controlled manner and how endosomal escape pathway contributes to initiation of immune responses.
The possible projects will involve: a) work with animal models and dendritic cells to characterise the contribution of the endosomal escape pathway to initiation of immune responses against pathogens or tumours, 2) characterisation of mutations identified in immunodeficient patients that are likely to result in defective endosomal escape pathway, and/or 3) biochemical reconstitution assays to understand how endosome leakiness is controlled in response to pathogen- or damage-associated signals. The position is best suited for an enthusiastic student in interested how immune responses are initiated at the molecular level.
Grotzke, J.E., P. Kozik*, J.-D. Morel, F. Impens, N. Pietrosemoli, P. Cresswell, S. Amigorena, and C. Demangel. (2017)
Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to- cytosol export.
Proceedings of the National Academy of Sciences. 114:E5910–E5919. doi:10.1073/pnas.1705242114.
Kozik, P.*, N.A. Hodson, D.A. Sahlender, N. Simecek, C. Soromani, J. Wu, L.M. Collinson, and M.S. Robinson. (2013)
A human genome-wide screen for regulators of clathrin-coated vesicle formation reveals an unexpected role for the V-ATPase.
Nature Cell Biology. 15:50–60. doi:10.1038/ncb2652.