title: Independent Proteolytic Activities Control the Stability and Size of Drosophila Inhibitor of Apoptosis 2 Protein.
abstract: The Drosophila immune deficiency pathway defends many bacterial pathogens and bears striking molecular similarities to the mammalian tumor necrosis factor signal transduction pathway. Orthologous inhibitors of apoptosis ubiquitin ligases act at a proximal stage of both responses to coordinate the assembly of signal transduction platforms that shape host immune responses. Despite the importance of inhibitor of apoptosis proteins within evolutionarily conserved innate immune responses, we know relatively little about the cellular machinery that controls inhibitor of apoptosis activity. In this study, we examined the molecular basis for inhibitor of apoptosis 2 protein regulation in the immune deficiency pathway. Our studies identified two distinct proteolytic events that determine the stability and composition of cellular inhibitor of apoptosis 2 protein pools. We found that apoptotic caspase activity cleaves inhibitor of apoptosis 2 at an N-terminal aspartate to generate a truncated protein that retains the ability to interact with immune deficiency pathway members. We also showed that a C-terminal ubiquitin ligase activity within inhibitor of apoptosis 2 directs the proteasomal destruction of full-length and truncated inhibitor of apoptosis 2 isoforms. These studies add to our appreciation of the regulation of innate immunity and suggest potential links between apoptotic caspases and innate defenses.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alta., Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guntermann
authors.forename: Brittany
authors.initials: B
authors.lastname: Fraser
authors.forename: Bart
authors.initials: B
authors.lastname: Hazes
authors.forename: Edan
authors.initials: E
authors.lastname: Foley
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000276:immunology*; D007113:Immunity, Innate; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D044767:Ubiquitin-Protein Ligases; D020169:Caspases; C118731:dronc protein, Drosophila; D046988:Proteasome Endopeptidase Complex