Caspar, a suppressor of antibacterial immunity in Drosophila

National Creative Research Initiatives Center for Cell Growth Regulation and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Kusong-dong, Yusong, Taejon 305-701, Korea.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2006; 103(44):16358-63. DOI: 10.1073/pnas.0603238103
Source: PubMed


Drosophila has a primitive yet highly effective innate immune system. Although the infection-dependent activation mechanisms of the Drosophila immune system are well understood, its inhibitory regulation remains elusive. To find novel suppressors of the immune system, we performed a genetic screening for Drosophila mutants with hyperactivated immune responses and isolated a loss-of-function mutant of caspar whose product is homologous to Fas-associating factor 1 in mammals. Interestingly, caspar mutant flies showed increased antibacterial immune responses including increased resistance to bacterial infection and a constitutive expression of diptericin, a representative antibacterial peptide gene. Conversely, ectopic expression of caspar strongly suppressed the infection-dependent gene expression of diptericin, which allowed bacterial outgrowth. Consistent with these physiological phenotypes, Caspar negatively regulated the immune deficiency (Imd)-mediated immune responses by blocking nuclear translocation of Relish, an NF-kappaB transcription factor. In addition, we further demonstrated that Dredd-dependent cleavage of Relish, a prerequisite event for the nuclear entry of Relish, is the target of the Caspar-mediated suppression of the Imd pathway. Remarkably, Caspar was highly specific for the Imd pathway and did not affect the Toll pathway, which is crucial for antifungal immunity. Collectively, our elucidation of an inhibitory mechanism of the Imd pathway by Caspar will provide a valuable insight into understanding complex regulatory mechanisms of the innate immune systems in both Drosophila and mammals.

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    • "The most striking evidence that IMD signalling is involved in directing anti - Plasmodium immunity was obtained by silencing caspar , an inhibitor of IMD sig - nalling through DREDD - dependent cleavage of REL2 - F ( Kim et al . 2006 ) . Caspar - silencing renders mosquitoes refractory to malaria parasites and it appears that activa - tion of the IMD pathway is more efficient in limiting P . falciparum infection than that of the murine malaria parasite , P . berghei ( Garver et al . 2009 ) . However , addi - tional work is needed to understand the precise mecha - ni"
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    • "The JNK pathway is also negatively regulated by relish. The Imd pathway is also generally inhibited by PGRP-LF via the JNK pathway [23] as well as caspar which blocks FADD-Dredd dependent cleavage of Relish, thereby preventing its translocation into the nucleus for stimulation of the antibacterial Diptericin genes as a form of feedback immune regulator in Drosophila [26]. By activating JNK, bacteria not only induce activation of antimicrobial peptide (AMP) genes, but also of genes encoding various cytokines and the cytoskeletal remodeling components required for phagocytosis [23]. "
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    • "Similarly, the RNA interference (RNAi)-mediated silencing of caspar efficiently prevents the development of the malaria parasite Plasmodium falciparum in the major malaria vectors, Anopheles stephensi and Anopheles albimanus (Garver et al., 2009). Caspar is homologous to the human Fasassociated factor 1 (FAF1; Kim et al., 2006). Human FAF1 "
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    ABSTRACT: Insect immune responses are precisely regulated to maintain immune balance. In this study, the Fas-associated factor 1 (FAF1) gene of Locusta migratoria manilensis, a homologue of the caspar gene that functions as a specific negative regulator in the antibacterial immunity pathway, was cloned. Gene expression analysis showed that FAF1 was expressed throughout the developmental stages and in all tested tissues, but its transcription levels varied significantly. Thus, FAF1 appears to be tightly regulated and is probably involved in multiple physiological processes. In addition, the antimicrobial peptide gene prolixicin was cloned and characterized. After bacterial challenge, prolixicin was rapidly up-regulated, whereas FAF1 was markedly down-regulated. This result was consistent with the observation that prolixicin was hyperactivated when FAF1 was suppressed by RNA interference. Moreover, after bacterial infection, the survival rate of FAF1-knockdown locusts was much higher than that of the wild-type. Taken together, these findings strongly suggest that FAF1 shares a similar function as caspar in Drosophila and may be involved in the negative regulation of antibacterial immunity in locusts.
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