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Gene Review

spz  -  spatzle

Drosophila melanogaster

Synonyms: CG6134, CT19282, Dmel\CG6134, Protein spaetzle, SPZ, ...
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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


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].


  1. Drosophila immunity: a large-scale in vivo RNAi screen identifies five serine proteases required for Toll activation. Kambris, Z., Brun, S., Jang, I.H., Nam, H.J., Romeo, Y., Takahashi, K., Lee, W.J., Ueda, R., Lemaitre, B. Curr. Biol. (2006) [Pubmed]
  2. Activation of Drosophila Toll during fungal infection by a blood serine protease. Ligoxygakis, P., Pelte, N., Hoffmann, J.A., Reichhart, J.M. Science (2002) [Pubmed]
  3. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., Hoffmann, J.A. Cell (1996) [Pubmed]
  4. Constitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. Levashina, E.A., Langley, E., Green, C., Gubb, D., Ashburner, M., Hoffmann, J.A., Reichhart, J.M. Science (1999) [Pubmed]
  5. Similarities between trunk and spätzle, putative extracellular ligands specifying body pattern in Drosophila. Casanova, J., Furriols, M., McCormick, C.A., Struhl, G. Genes Dev. (1995) [Pubmed]
  6. Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling. Weber, A.N., Tauszig-Delamasure, S., Hoffmann, J.A., Lelièvre, E., Gascan, H., Ray, K.P., Morse, M.A., Imler, J.L., Gay, N.J. Nat. Immunol. (2003) [Pubmed]
  7. Proteolytic processing of the Drosophila Spätzle protein by easter generates a dimeric NGF-like molecule with ventralising activity. DeLotto, Y., DeLotto, R. Mech. Dev. (1998) [Pubmed]
  8. Multiple isoforms of the Drosophila Spätzle protein are encoded by alternatively spliced maternal mRNAs in the precellular blastoderm embryo. DeLotto, Y., Smith, C., DeLotto, R. Mol. Gen. Genet. (2001) [Pubmed]
  9. Getting knotted: a model for the structure and activation of Spätzle. Mizuguchi, K., Parker, J.S., Blundell, T.L., Gay, N.J. Trends Biochem. Sci. (1998) [Pubmed]
  10. The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Halfon, M.S., Keshishian, H. Dev. Biol. (1998) [Pubmed]
  11. A family of proteins related to Spätzle, the toll receptor ligand, are encoded in the Drosophila genome. Parker, J.S., Mizuguchi, K., Gay, N.J. Proteins (2001) [Pubmed]
  12. New insights into Drosophila larval haemocyte functions through genome-wide analysis. Irving, P., Ubeda, J.M., Doucet, D., Troxler, L., Lagueux, M., Zachary, D., Hoffmann, J.A., Hetru, C., Meister, M. Cell. Microbiol. (2005) [Pubmed]
  13. Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic. Pelte, N., Robertson, A.S., Zou, Z., Belorgey, D., Dafforn, T.R., Jiang, H., Lomas, D., Reichhart, J.M., Gubb, D. Insect Biochem. Mol. Biol. (2006) [Pubmed]
  14. Constitutive expression of a single antimicrobial peptide can restore wild-type resistance to infection in immunodeficient Drosophila mutants. Tzou, P., Reichhart, J.M., Lemaitre, B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. Regulation of Easter activity is required for shaping the Dorsal gradient in the Drosophila embryo. Chang, A.J., Morisato, D. Development (2002) [Pubmed]
  16. Multiple extracellular activities in Drosophila egg perivitelline fluid are required for establishment of embryonic dorsal-ventral polarity. Stein, D., Nüsslein-Volhard, C. Cell (1992) [Pubmed]
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