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Drybp Contributes to the Negative Regulation of the Drosophila Imd Pathway

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Drybp Contributes to the Negative Regulation of the Drosophila Imd Pathway dRYBP Contributes to the Negative Regulation of the Drosophila Imd Pathway Ricardo Aparicio1., Claudine Neyen2., Bruno Lemaitre2, Ana Busturia1* 1 Centro de Biologı´a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas and Universidad Auto´noma de Madrid, Madrid, Spain, 2 Global Health Institute, School of Life Sciences, E´cole Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland 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. Citation: Aparicio R, Neyen C, Lemaitre B, Busturia A (2013) dRYBP Contributes to the Negative Regulation of the Drosophila Imd Pathway. PLoS ONE 8(4): e62052. doi:10.1371/journal.pone.0062052 Editor: Franc¸ois Leulier, Ecole Normale Supe´rieur de Lyon, France Received February 13, 2013; Accepted March 17, 2013; Published April 15, 2013 Copyright: ß 2013 Aparicio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Direccio´n General de Investigacio´n (BFU2008-01154) to A.B, the Consolider Ingenio 2010 Program of the Ministerio de Ciencia e Innovacio´n (CSD 2007-00008) to A.B., by an institutional grant from the Fundacio´n Ramo´n Areces to the Centro de Biologı´a Molecular Severo Ochoa, by the National Research Fund Luxembourg (AFR Postdoctoral Grant 08/037) to C.N., by the Bettencourt-Schueller Foundation to B.L., by the ERC Advanced Grant to C.N. and B.L., and the Swiss National Fund (3100A0-12079/1) to B.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. Introduction Drosophila NF-kB factor Relish, and its nuclear translocation [13]. Relish ultimately drives transcription of IMD-specific AMP Biological pathways involved in stress responses, like those genes such as Diptericin and Attacin-B as well as several regulatory associated with innate immunity, must quickly and efficiently Imd pathway components. modulate gene expression to ensure survival of the organism. Regulation of NF-kB pathway activity in both invertebrates and Drosophila uses the evolutionarily conserved host defense of innate vertebrates is achieved at multiple levels through ubiquitin- immunity to protect against microbial infection and relies mainly mediated post-translational modification of signaling components on the Toll and Imd pathways to regulate the expression of [14,15]. In Drosophila, selective linkage of mono- or poly-ubiquitin different AMP genes (for recent reviews see [1–3]). AMPs are chains triggering degradation or stabilization of Imd pathway constitutively expressed in immuno-competent epithelial tissues to components plays a crucial role in maintaining a balanced defend the body against infection [4,5]. Furthermore, upon immune response. IMD first undergoes cleavage by the caspase systemic microbial infection the Toll and Imd pathways up- DREDD, which itself is activated by poly-ubiquitylation [16,17]. regulate AMP production by the fat body and blood cells. Once The cleaved IMD protein is then tagged with K63-linked poly- the infection is controlled, AMP expression is down-regulated to ubiquitin chains by the E3 ligase dIAP2 in complex with E2 avoid deleterious immuno-pathological reactions [6]. conjugases Uev1a, dUbc13/Bendless and Effete [17,18], and The Imd signaling pathway is activated by infection with Gram- ubiquitylated IMD acts as an assembly platform for downstream negative bacteria and Gram-positive bacilli [7]. The activation is adaptors TAB2/dTAK1 [19]. Subsequent editing of K63- to K48- initiated upon detection of peptidoglycan (PGN) by PGRP-LC, a linked ubiquitin chains through the ubiquitin hydrolase dUsp36 member of the peptidoglycan recognition proteins, at the plasma ends signaling by targeting IMD for proteasomal degradation [20]. membrane [7–9]. Transduction of this signal requires ligand- As in vertebrates, ubiquitylation/deubiquitylation events also induced receptor oligomerization with subsequent assembly of a regulate stability of the Drosophila IKK complex (ird5/key) signaling complex containing IMD, DREDD, and dFADD [19,21–23]. DREDD-mediated cleavage of Relish is thought to receptor associated proteins [2,10–12]. The activation of this be held in check by Caspar, a protein with multiple ubiquitin- pathway leads to the post-translational modification of the related domains [24], and by DNR1, a RING-domain containing PLOS ONE | www.plosone.org 1 April 2013 | Volume 8 | Issue 4 | e62052 dRYBP Modulates Imd Pathway Signaling protein which binds to DREDD and has been proposed to target it Quantitative real-time PCR (qRT-PCR) for proteasomal degradation [25]. Finally, both intact and RNA was isolated from 10–15 adult female flies of appropriate processed Relish has been suggested to undergo ubiquitin- genotype. RNA extraction and RT reactions were performed as mediated degradation through SKPA, a member of the E3- previously described [31]. qRT-PCR was performed using ubiquitin ligase SCF complex [26]. FastStart Universal SYBR Green MasterRox (Roche) in an The dRYBP (drosophila Ring and YY1 Binding Protein) gene [27] Applied Biosystems 7900 Sequence Detector System. Quantified encodes a protein that is evolutionarily conserved in vertebrates mRNA levels were expressed as relative fold change normalized to (known as RYBP/DEDAF/YAF2) and that contains in its N- RpL32. The sequences of the primers and their efficiencies (in terminus a ubiquitin-binding domain of the NZF (Nucleoporin brackets) are the following: Zinc Finger) type [28]. Studies both in vertebrates and Drosophila RpL32 Forward: 59-GACGCTTCAAGGGACAGTATCTG- have described the phenotypic effects of high and low levels of 39, Reverse: 59-AAACGCGGTTCTGCATGAG-39 (1,89); dRYBP dRYBP expression and also its interactions with several proteins Forward: 59-CATGTTGACACCTGGCTCCTG-39, Reverse: 59- involved in a range of biological processes, including epigenetic CGAAGGTGATCGAGGAGAAC-39 (1,97) ; Dpt: Forward: 59- transcriptional regulation mediated by the Polycomb and trithorax GCTGCGCAATCGTTCTACT-39, Reverse: 59- groups of proteins [27,29–34]. Human RYBP/DEDAF has been TGGTGGAGTGGGCTTCATG-39 (1,98) ; AttB Forward: 59- shown to interact with DED (Death Effector Domain) containing CCTACAACAATGCTGGTCATGGT-39, Reverse: 59-CCTA- proteins [35,36] that mediate homotypic interactions important CAACAATGCTGGTCATGGT-39 (2,03); Relish Forward: 59- for the assembly and activation of apoptotic and inflammatory TTAGCGTGGCCAACACAATG-39, Reverse: 59-GAACTGC- complexes [37]. In Drosophila, high levels of dRYBP induces CATGTGGAGTGCAT-39 (1,98); PGRP-LC Forward: 59- apoptosis in imaginal disc cells and this apoptosis is dependent on GCATTCAATGGTGGTCCCA-39 Reverse: 59- dFADD and DREDD [31], two DED containing proteins [37] CCGGATCTTCGTGTTTGGAG-39 (1,97); imd Forward: 59- also involved in the IMD-mediated immune response in Drosophila TTCGGCTCCGTCTACAACTT-39, Reverse: 59-GTGATC- [10–12]. GATTATGGCCTGGT-39 (2,03); Dredd F: 59- In this work we show that dRYBP contributes to the negative CAAAAGGTGGGCCTCTGCT Reverse: 59-GTAGGTGG- regulation of the Imd signaling pathway. Notably, we have found CATCCGAGTGGT-39 (2,02); Tab-2 Forward: 59-TGTCATG- that dRYBP is required for the inhibition of the production of GAGGAATGCGATC-39, Reverse: 59-GCTTCTGACGCTC- AMPs upon systemic infection. We propose that dRYBP functions GATAGTGG-39 (1,97); TAK1 Forward: 59- in the immune response to promote ubiquitin-dependent degra- GATCTGAGTCCCAGCGAAAGC-39, Reverse: 59- dation of IMD-pathway components, among those the Relish CATCGCTCTTTGCGTTCGT-39 (1,96); ird-5 Forward: 59- protein. TAGTGATCCATTGGCGAAACC-39, Reverse: 59- GCTTGGTGGCAATTTCACG-39 (1,96); skpA Forward: 59- Materials And Methods CTCCCGAGGAAATACGCAAG-39, Reverse: 59- CGGGCGAAAAGTCCTTCTTA-39 (1,99); dIAP2 Forward: 59- Fly stocks ATGCAAGGTATGCTTGGACGA-39, Reverse: 59-TGATTG- CantonS were
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