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1.  Drosophila Microbiota Modulates Host Metabolic Gene Expression via IMD/NF-κB Signaling 
PLoS ONE  2014;9(4):e94729.
Most metazoans engage in mutualistic interactions with their intestinal microbiota. Despite recent progress the molecular mechanisms through which microbiota exerts its beneficial influences on host physiology are still largely uncharacterized. Here we use axenic Drosophila melanogaster adults associated with a standardized microbiota composed of a defined set of commensal bacterial strains to study the impact of microbiota association on its host transcriptome. Our results demonstrate that Drosophila microbiota has a marked impact on the midgut transcriptome and promotes the expression of genes involved in host digestive functions and primary metabolism. We identify the IMD/Relish signaling pathway as a central regulator of this microbiota-mediated transcriptional response and we reveal a marked transcriptional trade-off between the midgut response to its beneficial microbiota and to bacterial pathogens. Taken together our results indicate that microbiota association potentiates host nutrition and host metabolic state, two key physiological parameters influencing host fitness. Our work paves the way to subsequent mechanistic studies to reveal how these microbiota-dependent transcriptional signatures translate into host physiological benefits.
doi:10.1371/journal.pone.0094729
PMCID: PMC3986221  PMID: 24733183
2.  A Non-Redundant Role for Drosophila Mkk4 and Hemipterous/Mkk7 in TAK1-Mediated Activation of JNK 
PLoS ONE  2009;4(11):e7709.
Background
The JNK pathway is a mitogen-activated protein (MAP) kinase pathway involved in the regulation of numerous physiological processes during development and in response to environmental stress. JNK activity is controlled by two MAPK kinases (MAPKK), Mkk4 and Mkk7. Mkk7 plays a prominent role upon Tumor Necrosis Factor (TNF) stimulation. Eiger, the unique TNF-superfamily ligand in Drosophila, potently activates JNK signaling through the activation of the MAPKKK Tak1.
Methodology/Principal Findings
In a dominant suppressor screen for new components of the Eiger/JNK-pathway in Drosophila, we have identified an allelic series of the Mkk4 gene. Our genetic and biochemical results demonstrate that Mkk4 is dispensable for normal development and host resistance to systemic bacterial infection but plays a non-redundant role as a MAPKK acting in parallel to Hemipterous/Mkk7 in dTAK1-mediated JNK activation upon Eiger and Imd pathway activation.
Conclusions/Significance
In contrast to mammals, it seems that in Drosophila both MAPKKs, Hep/Mkk7 and Mkk4, are required to induce JNK upon TNF or pro-inflammatory stimulation.
doi:10.1371/journal.pone.0007709
PMCID: PMC2766050  PMID: 19888449
3.  DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells 
The Journal of Cell Biology  2007;179(7):1467-1480.
In addition to their well-known function in apoptosis, caspases are also important in several nonapoptotic processes. How caspase activity is restrained and shut down under such nonapoptotic conditions remains unknown. Here, we show that Drosophila melanogaster inhibitor of apoptosis protein 2 (DIAP2) controls the level of caspase activity in living cells. Animals that lack DIAP2 have higher levels of drICE activity. Although diap2-deficient cells remain viable, they are sensitized to apoptosis following treatment with sublethal doses of x-ray irradiation. We find that DIAP2 regulates the effector caspase drICE through a mechanism that resembles the one of the caspase inhibitor p35. As for p35, cleavage of DIAP2 is required for caspase inhibition. Our data suggest that DIAP2 forms a covalent adduct with the catalytic machinery of drICE. In addition, DIAP2 also requires a functional RING finger domain to block cell death and target drICE for ubiquitylation. Because DIAP2 efficiently interacts with drICE, our data suggest that DIAP2 controls drICE in its apoptotic and nonapoptotic roles.
doi:10.1083/jcb.200706027
PMCID: PMC2373516  PMID: 18166655
4.  The Drosophila Inhibitor of Apoptosis Protein DIAP2 Functions in Innate Immunity and Is Essential To Resist Gram-Negative Bacterial Infection▿  
Molecular and Cellular Biology  2006;26(21):7821-7831.
The founding member of the inhibitor of apoptosis protein (IAP) family was originally identified as a cell death inhibitor. However, recent evidence suggests that IAPs are multifunctional signaling devices that influence diverse biological processes. To investigate the in vivo function of Drosophila melanogaster IAP2, we have generated diap2 null alleles. diap2 mutant animals develop normally and are fully viable, suggesting that diap2 is dispensable for proper development. However, these animals were acutely sensitive to infection by gram-negative bacteria. In Drosophila, infection by gram-negative bacteria triggers the innate immune response by activating the immune deficiency (imd) signaling cascade, a NF-κB-dependent pathway that shares striking similarities with the pathway of mammalian tumor necrosis factor receptor 1 (TNFR1). diap2 mutant flies failed to activate NF-κB-mediated expression of antibacterial peptide genes and, consequently, rapidly succumbed to bacterial infection. Our genetic epistasis analysis places diap2 downstream of or in parallel to imd, Dredd, Tak1, and Relish. Therefore, DIAP2 functions in the host immune response to gram-negative bacteria. In contrast, we find that the Drosophila TNFR-associated factor (Traf) family member Traf2 is dispensable in resistance to gram-negative bacterial infection. Taken together, our genetic data identify DIAP2 as an essential component of the Imd signaling cascade, protecting the organism from infiltrating microbes.
doi:10.1128/MCB.00548-06
PMCID: PMC1636742  PMID: 16894030

Results 1-4 (4)