Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. TheDrosophila serpin Necrotic controls the innate immune response and is homologous to human α1-antitrypsin. We show thatnecrotic mutations that are identical to the Z-deficiency variant ofα 1-antitrypsin form urea-stable polymers in vivo. Thesenecrotic mutations are temperature sensitive, which is in keeping with the temperature-dependent polymerization of serpins in vitro and the role of childhood fevers in exacerbating liver disease in Z α-antitrypsin deficiency. In addition, we identify two nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an S>F amino-acid substitution equivalent to that found in Siiyama-variant antitrypsin (necS>F.UAS) fail to complement nec-null mutations and demonstrate a dominant temperature-dependent inactivation of the wild-type nec allele. Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo.

Keywords:
Necrotic, Serpin, Polymer, Z-variant α1-antitrypsin, Conformational disease, Drosophila
© 2003.
2003
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