Differences in activity between alpha and beta type I interferons explored by mutational analysis.
Type I interferon (IFN) subtypes alpha and beta share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, alpha and beta IFNs exhibit key differences in several biological properties. For example, IFN-beta, but not IFN-alpha, induces the association of tyrosine-phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor-associated, Janus kinase tyk2. To define the structural basis for these functional differences we produced human IFN-beta with point mutations and compared them to wild-type IFN-beta in assays that distinguish alpha and beta IFN subtypes. IFN-beta mutants with charged residues (N86K, N86E, or Y92D) introduced at two positions in the C helix lost the ability to induce the association of tyrosine-phosphorylated receptor chains and had reduced activity on tyk2-deficient cells. The combination of negatively charged residues N86E and Y92D (homologous with IFN-alpha8) increased the cross-species activity of the mutant IFN-betas on bovine cells to a level comparable to that of human IFN-alphas. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtype-specific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-alpha mutations. The effects of these mutations on IFN-beta activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.
Runkel
L
L
Institut de Génétique Moléculaire, CNRS, F-34293 Montpellier, Cedex 5, France.
Pfeffer
L
L
Lewerenz
M
M
Monneron
D
D
Yang
C H
CH
Murti
A
A
Pellegrini
S
S
Goelz
S
S
Uzé
G
G
Mogensen
K
K
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D004252:DNA Mutational Analysis; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016899:Interferon-beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D017354:Point Mutation; D013329:Structure-Activity Relationship
D016898:Interferon-alpha; D016899:Interferon-beta