Drosophila necrotic mutations mirror disease-associated variants of human serpins.
Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. The Drosophila serpin Necrotic controls the innate immune response and is homologous to human alpha(1)-antitrypsin. We show that necrotic mutations that are identical to the Z-deficiency variant of alpha(1)-antitrypsin form urea-stable polymers in vivo. These necrotic 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 alpha-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 (nec(S>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.
Green
Clare
C
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Brown
Gemma
G
Dafforn
Timothy R
TR
Reichhart
Jean-Marc
JM
Morley
Terri
T
Lomas
David A
DA
Gubb
David
D
D000818:Animals; D004330:Drosophila / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009336:Necrosis; D015843:Serpins / Q000235:genetics* / Q000502:physiology / Q000633:toxicity; D013696:Temperature; D014508:Urea / Q000378:metabolism
D015843:Serpins; D014508:Urea