Caspar, a suppressor of antibacterial immunity in Drosophila

Chungnam National University, Daiden, Daejeon, South 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.

Full-text preview

Available from:
  • Source
    • "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"
    [Show abstract] [Hide abstract]
    ABSTRACT: Nearly one million people are killed every year by the malaria parasite Plasmodium. Although the disease-causing forms of the parasite exist only in the human blood, mosquitoes of the genus Anopheles are the obligate vector for transmission. Here, we review the parasite life cycle in the vector and highlight the human and mosquito contributions that limit malaria parasite development in the mosquito host. We address parasite killing in its mosquito host and bottlenecks in parasite numbers that might guide intervention strategies to prevent transmission.
    Full-text · Article · Apr 2014 · Memórias do Instituto Oswaldo Cruz
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The fat body in invertebrates was shown to participate in energy storage and homeostasis, apart from its other roles in immune mediation and protein synthesis to mention a few. Thus, sharing similar characteristics with the liver and adipose tissues in vertebrates. However, vertebrate adipose tissue or fat has been incriminated in the pathophysiology of metabolic disorders due to its role in production of pro-inflammatory cytokines. This has not been reported in the insect fat body. The link between the fat body and adipose tissue was examined in this review with the aim of determining the principal factors responsible for resistance to inflammation in the insect fat body. This could be the missing link in the prevention of metabolic disorders in vertebrates, occasioned by obesity.
    Full-text · Article · Apr 2014 · Lipids in Health and Disease
  • Source
    • "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 "
    Z He · P Wang · H Shi · F Si · Y Hao · B Chen
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · May 2013 · Insect Molecular Biology
Show more