During a genome-wide RNAi screen, we isolated CG8580 as a gene involved in the innate immune response of Drosophila. CG8580, which we named Akirin, acts in parallel with the NF-κB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved and the human genome contains two homologues, one of which was able to rescue the loss of function phenotype in Drosophila cells. Akirins had a strict nuclear localization. Knockout of both Akirin homologues in mice revealed that one had an essential function downstream of Toll-like receptor, tumor necrosis factor and interleukin 1-β (IL-1β) signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.The innate immune system shields all metazoans against invading microorganisms. This well conserved defense mechanism relies on host-pathogen interactions between nonclonally distributed pattern recognition receptors in the host and pathogen-associated molecular patterns in microbes (reviewed in1-4). In contrast, the acquired immune system, based on selection of lymphocytes and their antigen-specific receptors, is specific to vertebrates. Drosophila has become an attractive model organism for the study of the innate immune system due to its well-established genetics, the absence of an acquired immune system and the striking conservation between its immune system and many mammalian Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to J-MR (e-mail: JM.Reichhart@ibmc.u-strasbg.fr). 4 current address, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki Aoba-ku, Sendai, 980-8578, Japan 5 AG and KM contributed equally to this work. AUTHOR CONTRIBUTIONS A.G., V.G., L.E.-C., and D.K. did the Drosophila experiments. K.M. and O.T. did the mouse experiments. S.A., M.B., O.T. and JM.R. conceived and directed the experiments, A.G., O.T., JA.H. and JM.R. wrote the paper. All authors contributed to manuscript criticism. Despite more than ten years of research since the initial discovery of the Imd mutation, the pathway that took its name is still not fully understood. We undertook a functional genome- (Fig. 1). The conservation is highest for the putative C and N-terminal domains. All sequences show a clear nuclear localization signal (NLS) located between residues 24 and 29 at the N-terminus ( Supplementary Fig. 1 online). We renamed the gene Akirin (Akirin1 and Akirin2 in the case of vertebrates) from the japanese `akiraka ni suru', which means `making things clear'. HHS Public Access RESULTS Identification of Drosophila and mice Akirin homologues Akirins are ubiquitously expressed nuclear proteinsMicroarray data in Flybase35 indicate that DmAkirin expression is ubiquitous. Similarly, an an...

Signalling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human malignancies. The Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway represents one such signalling cascade whose evolutionarily conserved roles include cell proliferation and haematopoiesis. Here we describe a systematic genome-wide survey for genes required for JAK/STAT pathway activity. Analysis of 20,026 RNA interference (RNAi)-induced phenotypes in cultured Drosophila melanogaster haemocyte-like cells identified interacting genes encoding 4 known and 86 previously uncharacterized proteins. Subsequently, cell-based epistasis experiments were used to classify these proteins on the basis of their interaction with known components of the signalling cascade. In addition to multiple human disease gene homologues, we have found the tyrosine phosphatase Ptp61F and the Drosophila homologue of BRWD3, a bromo-domain-containing protein disrupted in leukaemia. Moreover, in vivo analysis demonstrates that disrupted dBRWD3 and overexpressed Ptp61F function as suppressors of leukaemia-like blood cell tumours. This screen represents a comprehensive identification of novel loci required for JAK/STAT signalling and provides molecular insights into an important pathway relevant for human cancer. Human homologues of identified pathway modifiers may constitute targets for therapeutic interventions.

Innate immunity in vertebrates and invertebrates is of central importance as a biological programme for host defence against pathogenic challenges. To find novel components of the Drosophila immune deficiency (IMD) pathway in cultured haemocyte-like cells, we screened an RNA interference library for modifiers of a pathway-specific reporter. Selected modifiers were further characterized using an independent reporter assay and placed into the pathway in relation to known pathway components. Interestingly, the screen identified the Inhibitor of Apoptosis Protein 2 (IAP2) as being required for IMD signalling. Whereas loss of DIAP1, the other member of the IAP protein family in Drosophila, leads to apoptosis, we show that IAP2 is dispensable for cell viability in haemocyte-like cells. Cell-based epistasis experiments show that IAP2 acts at the level of Tak1 (transforming growth factor-b-activated kinase 1