title: The Drosophila inhibitor of apoptosis (IAP) DIAP2 is dispensable for cell survival, required for the innate immune response to gram-negative bacterial infection, and can be negatively regulated by the reaper/hid/grim family of IAP-binding apoptosis inducers.
abstract: Many inhibitor of apoptosis (IAP) family proteins inhibit apoptosis. IAPs contain N-terminal baculovirus IAP repeat domains and a C-terminal RING ubiquitin ligase domain. Drosophila IAP DIAP1 is essential for the survival of many cells, protecting them from apoptosis by inhibiting active caspases. Apoptosis initiates when proteins such as Reaper, Hid, and Grim bind a surface groove in DIAP1 baculovirus IAP repeat domains via an N-terminal IAP-binding motif. This evolutionarily conserved interaction disrupts DIAP1-caspase interactions, unleashing apoptosis-inducing caspase activity. A second Drosophila IAP, DIAP2, also binds Rpr and Hid and inhibits apoptosis in multiple contexts when overexpressed. However, due to a lack of mutants, little is known about the normal functions of DIAP2. We report the generation of diap2 null mutants. These flies are viable and show no defects in developmental or stress-induced apoptosis. Instead, DIAP2 is required for the innate immune response to Gram-negative bacterial infection. DIAP2 promotes cytoplasmic cleavage and nuclear translocation of the NF-kappaB homolog Relish, and this requires the DIAP2 RING domain. Increasing the genetic dose of diap2 results in an increased immune response, whereas expression of Rpr or Hid results in down-regulation of DIAP2 protein levels. Together these observations suggest that DIAP2 can regulate immune signaling in a dose-dependent manner, and this can be regulated by IBM-containing proteins. Therefore, diap2 may identify a point of convergence between apoptosis and immune signaling pathways.
authors.affiliation: Division of Biology, MC 156-29, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Jun R
authors.initials: JR
authors.lastname: Huh
authors.forename: Ian
authors.initials: I
authors.lastname: Foe
authors.forename: Israel
authors.initials: I
authors.lastname: Muro
authors.forename: Chun Hong
authors.initials: CH
authors.lastname: Chen
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
authors.forename: Soon Ji
authors.initials: SJ
authors.lastname: Yoo
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hay
mesh_terms: D000818:Animals; D017209:Apoptosis; D001424:Bacterial Infections / Q000517:prevention & control*; D016367:Baculoviridae / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism* / Q000382:microbiology; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism*
chemical_list: C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D051034:Inhibitor of Apoptosis Proteins; D009479:Neuropeptides; C108881:grim protein, Drosophila; C086973:rpr protein, Drosophila; D020169:Caspases