To characterize the function of the Drosophila dcaf12 in cell death, immune response, and longevity
Programmed cell death (PCD) plays a critical role in proper growth and morphogenesis of tissues during development. Defects in PCD are linked to a variety of degenerative and neoplastic diseases. Previously, we reported the identification of DCAF12 (DDB1 and Cul4-Associated Factors 12), an evolutionary conserved member of the WD40-motif repeat family of proteins, as a new regulator of developmental cell death in Drosophila. However, how exactly DCAF12 controls cell death and ensures developmental success has not been understood yet.
In Aim 1, to understand the mechanisms, we will identify the genes/pathways that interact with DCAF12 physically and/or genetically by proteomic and genomic approaches, including the dFOXO transcription factor. In addition to its role in developmental apoptosis, we have also discovered that dcaf12 is involved in immunity during development and aging in adults. The dcaf12 mutant larvae showed a strong suppression in antimicrobial peptide (AMP) expression after infection with pathogenic bacteria (Serratia marcescens). A transcriptomic analysis in larvae also showed that the basal expression of AMPs was strongly reduced (not shown).
In Aim 2, We will characterize the mechanism by which dcaf12 controls AMP production and regulates immunity during development. Preliminary data have revealed that DIAP2 (Drosophila Inhibitor of Apoptosis 2), a well-established regulator of immunity in Drosophila is misregulated in the dcaf12 mutant larvae (not shown). We will further characterize the interaction between DCAF12 and DIAP2 in the larval immune response. Surprisingly, while looking for dcaf12’s potential roles beyond developmental stages, we have also discovered that over-expression of dcaf12 in the abdominal fat body extends lifespan, suggesting a potential pleiotropic role of dcaf12 in Drosophila.
In Aim 3, using genomics and molecular genetics approaches, we will characterize the function of dcaf12 in adult flies, particularly in the regulation of aging and stress response.