Proteolytic processing of the Drosophila Spätzle protein by Easter generates a dimeric NGF-like molecule with ventralising activity

DeLotto, Yvonne; DeLotto, Robert

doi:10.1016/s0925-4773(98)00024-0

Cited by 180 publications

(143 citation statements)

References 21 publications

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“…The soluble recombinant Tc-Spz and Tc-Toll ectodomains were purified to homogeneity (36). The purified Tc-Spz pro-protein was synthesized as a disulfide-bonded dimer, consistent with previous Dm-Spz studies (41,42). The purified Tc-Toll ectodomain showed a molecular mass of 120 kDa, and its identity was confirmed by N-terminal sequencing (data not shown).…”

Section: +supporting

confidence: 65%

Innate immune response in insects: recognition of bacterial peptidoglycan and amplification of its recognition signal

Kim¹,

Park²,

Ha³

et al. 2008

BMB Reports

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Section: +supporting

confidence: 65%

Innate immune response in insects: recognition of bacterial peptidoglycan and amplification of its recognition signal

Kim¹,

Park²,

Ha³

et al. 2008

BMB Reports

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“…Indeed, the spaetzle͞Toll͞ tube͞pelle͞cactus gene cassette controls the expression of the antifungal peptide drosomycin (3). Spaetzle codes for a secreted protein of the cysteine-knot family of growth factors, which is activated by proteolytic cleavage (4,5). Processed Spaetzle is thought to bind to and activate the transmembrane receptor Toll, although direct interaction between the two proteins has not been reported to date.…”

mentioning

confidence: 99%

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

Tauszig

Jouanguy²,

Hoffmann³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

356

300

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Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll͞IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll͞IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.

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“…Activation of Toll is triggered by a proteolytically processed form of Spaetzle and not by the infectious agent itself Schneider et al, 1994;Lemaitre et al, 1996). The processed form of Spaetzle has structural similarities to mammalian growth factor and cytokine molecules (DeLotto and DeLotto, 1998 …”

mentioning

confidence: 99%

TLR4-dependent lipopolysaccharide signalling in epithelial cells is independent of extracellular protease activity

2002

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Summary Epithelial cells are the first cells that encounter infecting bacteria and, as such, they have developed several mechanisms for microbial protection. We have shown previously that bladder epithelial cells express the lipopolysaccharide (LPS) receptor Toll‐like receptor (TLR) 4 that enables a rapid cellular interleukin (IL)‐8 response when exposed to Escherichia coli and LPS. TLR4 belongs to a family of receptors that was initially identified in Drosophila, in which Toll is required for the immune response against fungi. Fungal exposure activates a series of serine proteases that process the protein Spaetzle to a cytokine‐like form that acts as a ligand for Toll. Here, we investigated whether a similar proteolytic cascade is required for human TLR activation. When screening a set of 18 protease inhibitors, three serine protease inhibitors (TPCK, TLCK and Pefabloc) were shown to inhibit LPS‐ and peptidoglycan‐induced IL‐8 production in TLR2‐ and TLR4‐positive bladder epithelial cells. However, they were equally effective inhibitors of IL‐1β‐induced signalling, indicating that their target(s) is/are located downstream of the TLRs. Further characterization showed that these inhibitors blocked IκB degradation but not phosphorylation in LPS‐stimulated cells, which suggests that the serine protease inhibitors target the 26S proteasome. Identical results were obtained on LPS‐stimulated monocytes. Based on these data, we find no evidence for the involvement of proteases upstream of TLRs in either epithelial cells or cells of the monocytic lineage.

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Proteolytic processing of the Drosophila Spätzle protein by Easter generates a dimeric NGF-like molecule with ventralising activity

Cited by 180 publications

References 21 publications

Innate immune response in insects: recognition of bacterial peptidoglycan and amplification of its recognition signal

Innate immune response in insects: recognition of bacterial peptidoglycan and amplification of its recognition signal

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

TLR4-dependent lipopolysaccharide signalling in epithelial cells is independent of extracellular protease activity

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