The IFNap family

In all mammalian species studied, the a IFNs are encoded by a family of closely related genes. In the human genome at least 14 active IFNa genes and 4 pseudogenes can be discriminated. In addition, in the human genome a subfamily of IFNa-related genes, called IFNcj genes, have been identified. The IFN'iu genes exhibit approximately 70% sequence homology with the other human IFNa genes and are mainly pseudogenes. In the mouse genome, 12 different complete IFNa genes have been isolated and characterized. Eleven of these encode biologically active proteins, the other is a pseudogene. The IFN« genes appear to be absent in mice. Multiple functional IFNa) genes have been described in cattle, horse and sheep. Recently, it was shown that the IFNa genes are also present in birds; the chicken genome as well as the duck genome contain at least 20 IFNa genes. Human IFNp is encoded by a single copy gene, which exhibits approximately 40% homology at the nucleotide level to the IFNa genes, and which is physically closely associated with the IFNa gene family. The mouse genome, in common with human, possesses a single IFNp gene, whereas cattle, sheep and pigs possess multiple IFNp genes.

In humans, type I IFN genes are located within the band p22 on the short arm of chromosome 9. Recently, the first complete physical map of the type I IFN gene cluster has been established. In mouse, type I IFN genes are clustered on chromosome 4; in hamster on chromosome 2q.

In all mammalian species studied, type I IFN genes are devoid of introns and encode proteins of 186190 amino acids, including a signal peptide of 23 amino acids. The IFNw proteins, which have approximately 60% sequence similarity to the IFNas, contain a C-terminal extension of 6 amino acids. All IFNas contain four cysteine residues (positions 1, 29, 99 and 1.39) which arc involved in disulfide bridges. An additional cysteine at position 86 is present in all murine, hamster and rat, and in some human subspecies. Most murine and a few human IF'Na subspecies contain an N-glycosylation site at position 78, and were shown to be glycosylated. The function of this glycosylation site is not understood, but it is not necessary for the biological activity of IFNs.

It is assumed that type I IFN genes share a common ancestor and that the IFNa gene family arose by repeated duplications of the ancestral a gene. The IFNa genes are relatively well conserved. Within a species the homology between the proteins is 70% or more. Between human and murine IFNa proteins the homology is 50-60%. Despite these structural similarities, IFNas are relatively species-specific: most human IFNs have only a low activity on mouse cells. However, certain mouse IFNas reveal high antiviral activity on hamster cells. Similarly, some hamster IFNas show antiviral activity on mouse cells.

In response to developmental stimuli, trophoblasts of ruminants and humans secrete a distinct class of IFNs, IFNt or trophoblast IFNs, which are involved in regulating maternal recognition of pregnancy. Several IFNt genes have been identified in sheep and cattle and more recently in humans. Structurally, the amino acid sequence of IFNt shows 30-70% homology to the type I IFNs from various species. Like the IFNoj proteins, the IFNt proteins contain a C-terminal extension of 6 amino acids. In addition, the tIFNs exhibit antiviral activity in common with other IFNs, and are able to bind the same receptor as IFNa, p and <o.

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