RpS6 is a substrate of PALLBEARER and a negative regulator of apoptotic cell clearance in Drosophila. Hui Xiao, Nathalie Franc. The Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA.
The swift removal of apoptotic cells by phagocytes is a critical event during development of all multi-cellular organisms. Yet, little is known about the molecular mechanisms regulating phagocytosis of apoptotic cells. We previously demonstrated a role for the ubiquitin-proteasome pathway in promoting efficient phagocytosis of apoptotic cells via the PALL-SCF complex composed of SkpA, dCullin-1 and the F-box protein PALLBEARER (PALL). In these complexes, the F-Box protein provides the substrate-binding function and specificity. Identifying PALL substrates is important to further our understanding of how the ubiquitin-proteasome promotes phagocytosis. We have identified the ribosomal protein RpS6 as a putative substrate for PALL by co-immunoprecipitation and mass spectrometry. RpS6 plays a role in immune cells, as RpS6 mutants have melanotic tumors, the sign of an aberrant immune response, as well as enlarged hemocytes. RpS6 knock-down enhances apoptotic cell clearance in S2 cells. Furthermore, overexpression of RpS6 in embryonic macrophages results in decreased phagocytosis in vivo. In addition, RpS6 genetically interacts with the pall null allele, which we recently generated by homologous recombination, further showing that RpS6 acts in the same pathway as pall and that RpS6 can suppress the pall mutant phenotype. We propose that RpS6 is a substrate of PALL that negative regulates phagocytosis of apoptotic cells, and are now investigating the detailed mechanisms of action of RpS6 in phagocytosis.