Abstract
The Drosophila Toll signalling pathway is partially homologous to the mammalian TLR innate immune pathway, but also has marked differences. The Drosophila Toll pathway is mainly activated by the endogenous ligand Spätzle, instead of by direct recognition of microbial molecules; and downstream signalling from adaptor molecules/kinases, MyD88/IRAKs, to the inhibitor of NF-κB (IκB) is a blackbox in Drosophila. These differences provide an interesting opportunity to decipher molecular mechanisms underlying microbial-independent activation of innate immunity. In our laboratory, we have performed ex vivo genome-wide RNAi screening and identified a HECT-type E3 ligase, Sherpa, as an essential component of intracellular Toll signalling; two protein kinases, Pitslre and Doa, as downstream kinases in the blackbox; and a Jumonji-like histone demethylase, Jarid2, as a transcription factor. Additionally, we found that the Drosophila larval peptide fraction has strong stimulatory activity on the Toll receptor. These findings and future analyses are likely to provide information on the as yet unclear molecular mechanisms of ‘sterile inflammation’ in mammals.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson KV, Jürgens G, Nüsslein-Volhard C (1985a) Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42:779–789
Anderson KV, Bokla L, Nüsslein-Volhard C (1985b) Establishment of dorsal-ventral polarity in the drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798
Belvin MP, Jin Y, Anderson KV (1995) Cactus protein degradation mediates Drosophila dorsal-ventral signaling. Genes Dev 9:783–793
Buchon N, Poidevin M, Kwon HM, Guillou A, Sottas V, Lee BL, Lemaitre B (2009) A single modular serine protease integrates signals from pattern-recognition receptors upstream of the Drosophila Toll pathway. Proc Natl Acad Sci U S A 106:12442–12447
Buss H, Handschick K, Jurrmann N, Pekkonen P, Beuerlein K, Müller H, Wait R, Saklatvala J, Ojala PM, Schmitz ML, Naumann M, Kracht M (2012) Cyclin-dependent kinase 6 phosphorylates NF-kB P65 at serine 536 and contributes to the regulation of inflammatory gene expression. PLoS One 7:e51847
Chen G-Y, Tang J, Zheng P, Liu Y (2009) CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323:1722–1725
El Chamy L, Leclerc V, Caldelari I, Reichhart JM (2008) Sensing of ‘danger signals’ and pathogen-associated molecular patterns defines binary signaling pathways ‘upstream’ of Toll. Nat Immunol 9:1165–1170
Ferrandon D, Imler JL, Hetru C, Hoffmann JA (2007) The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections. Nat Rev Immunol 7:862–874
Flotho A, Melchior F (2013) Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 82:357–385
Gobert V, Gottar M, Matskevich AA, Rutschman S, Royet J, Belvin M, Hoffmann JA (2003) Dominique Ferrandon, Dual activation of the Drosophila toll pathway by two pattern recognition receptors. Science 302:2126–2130
Goto A, Yano T, Terashima J, Iwashita S, Oshima Y, Kurata S (2010) Cooperative regulation of the induction of the novel antibacterial Listericin by peptidoglycan recognition protein LE and the JAK-STAT pathway. J Biol Chem 285:15731–15738
Gottar M, Gobert V, Matskevich AA, Reichhart JM, Wang C, Butt TM, Belvin M, Hoffmann JA, Ferrandon D (2006) Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell 127:1425–1437
Hauling T, Krautz R, Markus R, Volkenhoff A, Kucerova L, Theopold U (2014) A Drosophila immune response against Ras-induced overgrowth. Biol Open 3:250–260
Igaki T, Yamamoto-Goto Y, Tokushige N, Kanda H, Miura M (2002) Down-regulation of DIAP1 triggers a novel Drosophila cell death pathway mediated by Dark and DRONC. J Biol Chem 277:23103–23106
Ip YT, Reach M, Engstrom Y, Kadalayil L, Cai H, Gonzalez-Crespo S, Tatei K, Levine M (1993) Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 75:753–763
Jang IH, Chosa N, Kim SH, Nam HJ, Lemaitre B, Ochiai M, Kambris Z, Brun S, Hashimoto C, Ashida M, Brey PT, Lee WJ (2006) A Spatzle-processing enzyme required for toll signaling activation in Drosophila innate immunity. Dev Cell 10:45–55
Kanoh H, Tong L-L, Kuraishi T, Suda Y, Momiuchi Y, Shishido F, Kurata S (2015a) Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults. Sci Signal 8:ra107
Kanoh H, Kuraishi T, Tong LL, Watanabe R, Nagata S, Kurata S (2015b) Ex vivo genome-wide RNAi screening of the Drosophila Toll signaling pathway elicited by a larva-derived tissue extract. Biochem Biophys Res Commun 467:400–406
Kleino A, Silverman N (2014) The Drosophila IMD pathway in the activation of the humoral immune response. Dev Comp Immunol 42:25–35
Kruidenier L, Chung C, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, Eberhard D, Hutchinson S, Jones E, Katso R, Leveridge M, Mander PK, Mosley J, Ramirez-Molina C, Rowland P, Schofield CJ, Sheppard RJ, Smith JE, Swales C, Tanner R, Thomas P, Tumber A, Drewes G, Oppermann U, Patel DJ, Lee K, Wilson DM (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–408
Kurata S (2014) Peptidoglycan recognition proteins in Drosophila immunity. Dev Comp Immunol 42:36–41
Lemaitre B, Hoffmann J (2007) The host defense of Drosophila melanogaster. Annu Rev Immunol 25:697–743
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983
Manfruelli P, Reichhart JM, Steward R, Hoffmann JA, Lemaitre B (1999) A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF. EMBO J 18:3380–3391
Marek LR, Kagan JC (2012) Phosphoinositide binding by the Toll adaptor dMyD88 controls antibacterial responses in Drosophila. Immunity 36:612–622
McIlroy G, Istvan F, Aurikko J, Wentzell JS, Lim MA, Fenton JC, Gay NJ, Hidalgo A (2013) Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nat Neurosci 16:1248–1256
Michel T, Reichhart JM, Hoffmann JA, Royet J (2001) Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature 414:756–759
Ming M, Obata F, Kuranaga E, Miura M (2014) Persephone/Spätzle Pathogen Sensors Mediate the Activation of Toll Receptor Signaling in Response to Endogenous Danger Signals in Apoptosis-deficient Drosophila. J Biol Chem 289:7558–7568
Nakamoto M, Moy RH, Xu J, Bambina S, Yasunaga A, Shelly SS, Gold B, Cherry S (2012) Virus recognition by Toll-7 activates antiviral autophagy in Drosophila. Immunity 36:658–667
Qiang X, Yang W-L, Wu R, Zhou M, Jacob A, Dong W, Kuncewitch M, Ji Y, Yang H, Wang H, Fujita J, Nicastro J, Coppa GF, Tracey KJ, Wang P (2013) Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med 19:1489–1495
Reach M, Galindo RL, Towb P, Allen JL, Karin M, Wasserman SA (1996) A gradient of cactus protein degradation establishes dorsoventral polarity in the Drosophila embryo. Dev Biol 180:353–364
Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarisation and host responses against helminth infection. Nat Immunol 11:936–944
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
Sun H, Bristow BN, Qu G, Wasserman SA (2002) A heterotrimeric death domain complex in Toll signaling. Proc Natl Acad Sci U S A 99:12871–12876
Sun H, Towb P, Chiem DN, Foster BA, Wasserman SA (2004) Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning. EMBO J 23:100–110
Sutcliffe B, Forero MG, Zhu B, Robinson IM, Hidalgo A (2013) Neuron-Type Specific Functions of DNT1, DNT2 and Spz at the Drosophila Neuromuscular Junction. PLoS One 8:e75902
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 14:805–820
Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL (2002) Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat Immunol 3:91–97
Towb P, Galindo RL, Wasserman SA (1998) Recruitment of Tube and Pelle to signaling sites at the surface of the Drosophila embryo. Development 125:2443–2450
Valanne S, Wang JH, Ramet M (2011) The Drosophila Toll signaling pathway. J Immunol 186:649–656
Watanabe Y, Nakamura T, Ishikawa S, Fujisaka S, Usui I, Tsuneyama K, Ichihara Y, Wada T, Hirata Y, Suganami T, Izaki H, Akira S, Miyake K, Kanayama H, Shimabukuro M, Sata M, Sasaoka T, Ogawa Y, Tobe K, Takatsu K, Nagai Y (2012) The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation. Diabetes 61:1199–1209
Weber AN, Tauszig-Delamasure S, Hoffmann JA, Lelievre E, Gascan H, Ray KP, Morse MA, Imler JL, Gay NJ (2003) Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Nat Immunol 4:794–800
Acknowledgments
We are grateful to all members of the CREST/PRESTO Chronic Inflammation research group for discussions.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Additional information
Funding
This work was supported by grants from the Japan Science and Technology Agency (JST).
Author contributions
T. K., H. K, Y. M., and H. K. contributed equally to this work. T. K., H. K, Y. M., and H. K. wrote the draft. H. K. drew the figures. T. K. managed the writing. T. K., H. K, Y. M., H. K., and S. K. completed the manuscript.
Competing Interests
The authors declare no conflict of interest.
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Kuraishi, T., Kanoh, H., Momiuchi, Y., Kenmoku, H., Kurata, S. (2016). The Drosophila Toll Pathway: A Model of Innate Immune Signalling Activated by Endogenous Ligands. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_10
Download citation
DOI: https://doi.org/10.1007/978-4-431-56068-5_10
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-56066-1
Online ISBN: 978-4-431-56068-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)