Hepatocyte nuclear factor 1alpha controls the expression of terminal complement genes.
The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling their tissue-specific expression have not been elucidated. In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor 1alpha (HNF1alpha) fail to transcribe C5 and C8A complement genes. In addition, mRNAs encoding for several other terminal complement components or subunits are expressed at lower levels, including C8beta, C8gamma, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1alpha-deficient mice showed negligible hemolytic activity of both C5 and C8alpha-gamma subunits. The activity of C8beta was severely affected despite only a 50% reduction in C8beta mRNA levels in the liver. This is reminiscent of C8alpha-gamma-deficient patients who accumulate extremely low levels of the C8beta subunit. Our results demonstrate that HNF1alpha plays a key role in the expression of C5 and C8A genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation.
Pontoglio
M
M
Unité des Virus Oncogènes, Centre National de la Recherche Scientifique URA 1644, Département de Biotechnologie, Institut Pasteur, 75724 Paris cedex 15, France. marcop@pasteur.fr
Pausa
M
M
Doyen
A
A
Viollet
B
B
Yaniv
M
M
Tedesco
F
F
D000818:Animals; D001483:Base Sequence; D002843:Chromatin; D003182:Complement C5 / Q000235:genetics* / Q000276:immunology; D003185:Complement C8 / Q000235:genetics* / Q000276:immunology; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D005820:Genetic Testing; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
C087169:C8G protein, human; D002843:Chromatin; D003182:Complement C5; D003185:Complement C8; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta