Abstract
The Drosophila humoral innate immune response fights infection by producing antimicrobial peptides (AMPs) through the microbe-specific activation of the Toll or the Imd signaling pathway. Upon systemic infection, the production of AMPs is both positively and negatively regulated to reach a balanced immune response required for survival. Here, we report the function of the dRYBP (drosophila Ring and YY1 Binding Protein) protein, which contains a ubiquitin-binding domain, in the Imd pathway. We have found that dRYBP contributes to the negative regulation of AMP production: upon systemic infection with Gram-negative bacteria, Diptericin expression is up-regulated in the absence of dRYBP and down-regulated in the presence of high levels of dRYBP. Epistatic analyses using gain and loss of function alleles of imd, Relish, or skpA and dRYBP suggest that dRYBP functions upstream or together with SKPA, a member of the SCF-E3-ubiquitin ligase complex, to repress the Imd signaling cascade. We propose that the role of dRYBP in the regulation of the Imd signaling pathway is to function as a ubiquitin adaptor protein together with SKPA to promote SCF-dependent proteasomal degradation of Relish. Beyond the identification of dRYBP as a novel component of Imd pathway regulation, our results also suggest that the evolutionarily conserved RYBP protein may be involved in the human innate immune response.
Highlights
Biological pathways involved in stress responses, like those associated with innate immunity, must quickly and efficiently modulate gene expression to ensure survival of the organism
We investigated whether the dRYBP gene could be regulating the expression of antimicrobial peptides (AMPs), which are always induced upon activation of the immune response. mRNA expression levels of Diptericin (Dpt), an AMP normally induced upon activation of the Imd pathway [41], were measured by qRTPCR in dRYBP null adult flies [30]
Upon infection with the Gram-negative bacterium Erwinia carotovora carotovora 15 (Ecc15), Dpt expression was significantly increased beyond wild type levels after 8 h of infection in dRYBP1and dRYBPD55 homozygous mutant flies, as well as in flies of dRYBP1 or dRYBPD55 genotype over dRYBP genomic deficiencies excluding background effects (Fig. 1A, 8 hours). dRYBP mutants showed a normal return to baseline at 24h after challenge (Fig 1A, 24 hours)
Summary
Biological pathways involved in stress responses, like those associated with innate immunity, must quickly and efficiently modulate gene expression to ensure survival of the organism. The activation is initiated upon detection of peptidoglycan (PGN) by PGRP-LC, a member of the peptidoglycan recognition proteins, at the plasma membrane [7,8,9] Transduction of this signal requires ligandinduced receptor oligomerization with subsequent assembly of a signaling complex containing IMD, DREDD, and dFADD receptor associated proteins [2,10,11,12]. The activation of this pathway leads to the post-translational modification of the Drosophila NF-kB factor Relish, and its nuclear translocation [13]. Relish drives transcription of IMD-specific AMP genes such as Diptericin and Attacin-B as well as several regulatory Imd pathway components
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