Disease relevance of spz

• During the immune response, Spz is thought to be processed by secreted serine proteases (SPs) present in the hemolymph that are activated by the recognition of gram-positive bacteria or fungi . In the present study, we have used an in vivo RNAi strategy to inactivate 75 distinct Drosophila SP genes [1].
• Drosophila host defense to fungal and Gram-positive bacterial infection is mediated by the Spaetzle/Toll/cactus gene cassette [2].

High impact information on spz

• The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults [3].
• Spaetzle was cleaved by proteolytic enzymes to its active ligand form shortly after immune challenge, and cleaved Spaetzle was constitutively present in Spn43Ac-deficient flies [4].
• Furthermore, the carboxy-terminal domain of trk has a similar arrangement of cysteines to that of spz [5].
• The extracellular protein Spätzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila [6].
• We show here that the mature form of Spätzle triggers a Toll-dependent immune response after injection into the hemolymph of flies [6].

Biological context of spz

• Biochemical interactions underlying the generation of the ventralising signal during Drosophila embryogenesis were investigated by the expression of recombinant Easter and Spätzle proteins [7].
• Here we show that the spätzle gene encodes at least ten different protein isoforms as a result of complex alternative splicing in precellular blastoderm embryos [8].
• Proteolytically cleaved Spätzle could therefore dimerize and activate the Toll receptor by inducing receptor dimerization [9].
• We find that spätzle, tube, and pelle, but not easter, are necessary for muscle development [10].
• A family of proteins related to Spätzle, the toll receptor ligand, are encoded in the Drosophila genome [11].

Anatomical context of spz

• Multiple isoforms of the Drosophila Spätzle protein are encoded by alternatively spliced maternal mRNAs in the precellular blastoderm embryo [8].
• Spätzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll [6].
• A second compelling observation was that following infection, the gene encoding the cytokine Spatzle was uniquely upregulated in haemocytes and not the fat body [12].

Associations of spz with chemical compounds

• Comparative modelling suggests that Spätzle adopts a cystine-knot fold and forms a dimer that contains a single, intermolecular disulphide bridge [9].
• Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle [13].

Physical interactions of spz

• In dorsal-ventral patterning, the most widely accepted model of the pathway places Spätzle at the end of a ventrally restricted protease cascade that results in the proteolytic processing of the precursor form of Spätzle to an active ligand which is thought to bind to the Toll receptor [8].

Enzymatic interactions of spz

• An active form of Easter protease cleaves the Spätzle protein, generating a carboxyterminal polypeptide fragment which, when microinjected into the perivitelline space of a spätzle deficient embryo, directs production of ventrolateral pattern elements [7].

Regulatory relationships of spz

• It has been proposed that Toll does not function as a pattern recognition receptor per se but is activated through a cleaved form of the cytokine Spaetzle [2].

Other interactions of spz

• Here, we report the identification of five novel SPs that function in an extracellular pathway linking the recognition proteins GNBP1 and PGRP-SA to Spz [1].
• We have expressed AMP genes via the control of the UAS/GAL4 system in imd; spätzle double mutants that do not express any known endogenous AMP gene [14].
• Spätzle is synthesized as a pro-protein and is processed to a functional form by a serine protease [6].
• The easter gene encodes a serine protease that generates processed Spätzle, which is proposed to act as the Toll ligand [15].

Analytical, diagnostic and therapeutic context of spz

• RNA microinjection experiments demonstrate that three isoforms completely rescue embryos from spätzle null mothers, while most of the others rescue to a lesser extent [8].
• Here, by transplantation of perivitelline fluid we demonstrate the presence of three separate activities present in the perivitelline fluid that can restore dorsal-ventral polarity to mutant easter, snake, and spätzle embryos, respectively [16].
• Sequence analyses show that Spätzle, the Drosophila melanogaster Toll-receptor ligand, shows striking similarity to nerve growth factor and coagulogen [9].

References