Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic.
The Drosophila Necrotic protein is a serine proteinase inhibitor, which regulates the Toll-mediated innate immune response. Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle. Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure. We show here that cleavage of this N-terminal extension occurs following immune challenge. This modification is blocked in PGRP-SA(semmelweiss) mutants after Gram-positive bacterial challenge and in persephone mutants after fungal or Gram-positive bacterial challenge, indicating that activation of either of the Toll pathway upstream branches induces N-terminal cleavage of the serpin. The absolute requirement of persephone gene product for this cleavage indicates that Gram-positive bacteria activate a redundant set of proteinases upstream of Toll. Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases. We found a 13-fold increase in the specificity of the core serpin over that of full-length Necrotic for one of the tested proteinases (porcine pancreatic elastase). This finding indicates that cleavage of the Necrotic amino-terminal extension might modulate Toll activation following the initial immune response.
Pelte
Nadège
N
Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67000 Strasbourg, France.
Robertson
Andrew S
AS
Zou
Zhen
Z
Belorgey
Didier
D
Dafforn
Timothy R
TR
Jiang
Haobo
H
Lomas
David
D
Reichhart
Jean-Marc
JM
Gubb
David
D
D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D011487:Protein Conformation; D015843:Serpins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
D029721:Drosophila Proteins; D015843:Serpins; C417282:nec protein, Drosophila