Characterization of Spz5 as a novel ligand for Drosophila Toll-1 receptor

Nonaka, Saori; Kawamura, Koichiro; Hori, Ariyuki; Salim, Emil; Fukushima, Kazuki; Nakanishi, Yoshinobu; Kuraishi, Takayuki

doi:10.1016/j.bbrc.2018.10.096

Cited by 17 publications

(16 citation statements)

References 37 publications

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“…In Drosophila, six spätzle homologues (Spz1-6) have been identified, including the first identified spätzle gene, spz-1, which encodes a protein containing neurotrophin-like cystine-knot domains [15]. The study of the interaction of spätzle family proteins with each other and with Toll receptors during the activation of AMP gene expression showed that the binding of Spz-1, -2, and -5 to the Toll-1 and Toll-7 ectodomains promotes the activation of drosomycin and several other AMP genes [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

TmSpz4 Plays an Important Role in Regulating the Production of Antimicrobial Peptides in Response to Escherichia coli and Candida albicans Infections

Edosa

Keshavarz

et al. 2020

IJMS

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Spätzle family proteins activate the Toll pathway and induce antimicrobial peptide (AMP) production against microbial infections. However, the functional importance of Tmspätzle4 (TmSpz4) in the immune response of Tenebrio molitor has not been reported. Therefore, here, we have identified and functionally characterized the role of TmSpz4 against bacterial and fungal infections. We showed that TmSpz4 expression was significantly induced in hemocytes at 6 h post-injection with Escherichia coli, Staphylococcus aureus, and Candida albicans. TmSpz4 knock-down significantly reduced larval survival against E. coli and C. albicans. To understand the reason for the survivability difference, the role of TmSpz4 in AMP production was examined in TmSpz4-silenced larvae following microbe injection. The AMPs that are active against Gram-negative bacteria, including TmTenecin-2, TmTenecin-4, TmAttacin-1a, TmDefensin-2, and TmCecropin-2, were significantly downregulated in response to E. coli in TmSpz4-silenced larvae. Similarly, the expression of TmTenecin-1, TmTenecin-3, TmThaumatin-like protein-1 and -2, TmDefensin-1, TmDefensin-2, and TmCecropin-2 were downregulated in response to C. albicans in TmSpz4-silenced larvae. In addition, the transcription factor NF-κB (TmDorX1 and TmDorX2) expression was significantly suppression in TmSpz4-silenced larvae. In conclusion, these results suggest that TmSpz4 plays a key role in regulating immune responses of T. molitor against to E. coli and C. albicans.

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Section: Introductionmentioning

confidence: 99%

TmSpz4 Plays an Important Role in Regulating the Production of Antimicrobial Peptides in Response to Escherichia coli and Candida albicans Infections

Edosa

Keshavarz

et al. 2020

IJMS

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“…We screened the DDPs on the Drosophila assay system for cytotoxicity, inhibitory activity of innate immune signalling and insecticidal activity 57 . The cytotoxicity of the DDPs was evaluated using two cell lines, embryonic macrophage-derived DL1 cells [58][59][60] and larval blood cell-derived l(2)mbn cells 61 , and their IC 50 values are listed in Supplementary Table 23. Most DDPs except for compounds with the enone at the C 5 unit (7, 19 and 25) showed potent antiproliferative activity, and they affected DL1 cell lines more potently.…”

Section: Resultsmentioning

confidence: 99%

Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

et al. 2020

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A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.

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“…While Drosophila Spz1 is able to stimulate GAM moderately in Aag2 cells, this property is not shared by Spz1C. In Drosophila, Spz5 is recognised by Toll1, Toll6 and Toll7 (Chowdhury et al, 2019;Foldi et al, 2017;Nonaka et al, 2018). Given that Aag2 cells express other members relating to the Toll family of receptors (Fig.…”

Section: Spz1c Activates the Production Of Antimicrobial Peptides In Aag2 Cellsmentioning

confidence: 97%

“…By contrast, Spz5 is secreted as a mature form without the prodomain. Growing evidence suggest promiscuity in ligand binding, with Toll1 and Toll7 recognising Spz1, Spz2 and Spz5 as well as vesicular stomatitis virus (VSV) virions (Chowdhury et al, 2019;Nakamoto et al, 2012;Nonaka et al, 2018;Shelly et al, 2009), while Toll6 senses Spz2 and Spz5 (Foldi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti

Saucereau

Wilson

Moncrieffe

et al. 2021

Preprint

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A. aegypti has evolved to become an efficient vector of Dengue viruses among other arboviruses despite Toll-regulated infection levels. Interestingly, both Toll and its ligand Spaetzle (Spz) have undergone gene duplication in A. aegypti raising the possibility of neofunctionalization and mutualism to develop between arboviruses and mosquitoes. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A-Spz1C complexes that display transient but specific interactions. Binding of the first ligand alters receptor-receptor interactions and promotes asymmetric contacts in the vicinity of the Z-loop in Toll5A. This conformation then restricts binding of a second ligand, while bridging the C termini that promote signalling. In contrast, increased receptor concentrations promote inactivating head-to-head receptor assemblies. We also found that Spz1C differs from orthologous and paralogous cytokines in their transcriptional responses upon A. aegypti Aag2 cell stimulation. Interestingly, Spz1C uniquely controls genes involved in innate immunity, lipid metabolism and tissue regeneration. Given the remarkable DENV-induced expression patterns of these proteins, our data rationalises how Spz1C upregulation might promote innate immunity in the midgut, and Toll5A upregulation, viral tolerance in the salivary glands.

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Characterization of Spz5 as a novel ligand for Drosophila Toll-1 receptor

Cited by 17 publications

References 37 publications

TmSpz4 Plays an Important Role in Regulating the Production of Antimicrobial Peptides in Response to Escherichia coli and Candida albicans Infections

TmSpz4 Plays an Important Role in Regulating the Production of Antimicrobial Peptides in Response to Escherichia coli and Candida albicans Infections

Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti

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