Annexin A1 is an immune-modulatory protein that acts through a family of
pattern recognition receptors expressed on leukocytes, the formyl peptide
receptors (FPRs). Interaction of annexin A1 with FPRs triggers intracellular
signalling cascades and inhibits the extravasation of innate immune cells
into inflamed tissue. As a FPR ligand annexin A1 occurs outside of cells.
However, it is a cytosolic protein with no signal sequence directing it to the
classical secretory pathway and the mechanism(s) underlying the release
(‘secretion’) of annexin A1 have not been elucidated. This project aims at
deciphering these mechanisms. In the previous funding period we could
show that induction of apoptosis triggers the release of annexin A1 and that
this process is accompanied by proteolytic processing of the protein
generating N-terminal peptides that function as FPR ligands. Moreover, we
characterized structural determinants mediating the association of annexin
A1 with multivesicular endosomes as this association most likely underlies
the release via secretory lysosomes/endosomes. We now want to analyse
whether induction of apoptosis triggers a change in the association of
annexin A1 with endosomes and how this relates to its secretion.
Furthermore, we plan to characterize the role of annexin A1 cleavage in
endosome translocation and secretion. Mechanisms elucidated will be
compared to those involved in the release of the pro-inflammatory proteins
studied within the network (IL-1ß, S100A8/A9, FGF-2) and will also be analysed for their potential contribution to autoinflammation.