Activation of the immune system against pathogenic organisms involves the internalization of infectious material into macrophages, the processing and presentation of pathogen-derived peptides to T lymphocytes and the activation of these T lymphocytes in order to carry out effector functions. The internalization and processing of pathogens, is regulated through signal transduction processes, many of which involve cell surface receptor molecules. My laboratory is studying the signal transduction processes that originate from the plasma membrane and operate at the interface between the plasma membrane and the leukocyte cytoskeleton. We have been studying the leukocyte specific molecule coronin 1 (also termed P57 or TACO, for Tryptophan Aspartate containing COat protein), that functions in the regulation of the interaction of the leukocyte membrane with the cytoskeleton. Coronin 1 is a member of the WD repeat protein family of coronins. Coronins constitute a family of proteins widely expressed in the eukaryotic kingdom that are characterized by the presence of a large WD repeat region. Whereas in Dictyostelium, which contains a single coronin gene, coronin is involved in F-actin dependent processes such as phagocytosis, cell migration and cytokinesis (1), in mammalian cells no biological activity has been so far assigned to any of the coronin homologues. Coronin 1 was originally defined as a molecule that is recruited to the phagosome upon bacterial infection. Whereas in uninfected macrophages, coronin 1 localizes at the cell cortex, upon infection of pathogenic mycobacteria such as M. tuberculosis, coronin 1 is actively retained and blocks the fusion of the mycobacterial phagosomes with lysosomes. As a result, pathogenic mycobacteria avoid destruction within macrophage lysosomes allowing these to survive for prolonged times within infected cells (see Figure 1 and (2, 3)). Furthermore, we found that coronin 1 forms homotrimers and assembles with membrane via cholesterol (4, 5). Since cholesterol-enriched plasma membrane domains are involved in the organization of signaling complexes, these findings suggest that coronin 1 may participate in signal transduction cascades that are involved in intracellular trafficking. Using a number of biochemical and cell biological approaches, we are aiming to decipher the role for coronin 1 in leukocytes. 1. E. L. de Hostos, B. Bradtke, F. Lottspeich, R. Guggenheim, G. Gerisch, Embo J 10, 4097 (Dec, 1991). 2. G. Ferrari, M. Naito, H. Langen, J. Pieters, Cell 97, 435 (1999). 3. E. N. Houben, L. Nguyen, J. Pieters, Curr Opin Microbiol 9, 76 (2006). 4. R. A. Kammerer et al., Proc Natl Acad Sci U S A 102, 13891 (2005). 5. J. Gatfield, J. Pieters, Science 288, 1647 (2000).