Influence of mannose receptor ubiquitination and TLR signaling on antigen translocation from endosomes into the cytoplasm for cross-presentation

• Antragsteller: Professor Dr. Sven Burgdorf
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2008 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 91058073

For cross-presentation, antigens need to be transported from an endosomal compartment into the cytoplasm, a process that is only partially understood. In a first phase of this grant application, we demonstrated that poly-ubiquitination of the Mannose Receptor (MR), an endocytic receptor that targets its ligands specifically towards cross-presentation, is required for such antigen transport. Poly-ubiquitination of the MR mediated the recruitment of p97, an enzyme that provided the energy for antigen translocation, towards the endosomal membrane. Additionally, we identified TSG101 as a dominant negative inhibitor of MR poly-ubiquitination, p97 recruitment and antigen translocation into the cytosol, and hence as an important regulator of cross-presentation. Previous work by our group demonstrated that, after antigen transport into the cytoplasm and proteasomal degradation, antigenderived peptides are translocated by endosomal TAP into the same endosomes, where loading onto MHC I molecules occurs. Such spatial separation compared to MHC I presentation in the ER implies the use of a distinct set of proteasomes in direct proximity to such endosomes. Since p97 during dislocation at the ER recruits proteasomes towards the ER membrane, we would like to investigate in the second part of this proposal whether p97 mediates the recruitment of proteasome subunits also at the endosomal membrane and whether such recruitment is essential for cross-presentation.

• DFG-Verfahren: Sachbeihilfen