Identification of two regions within the cytoplasmic domain of the human interferon-γ receptor required for function*

Functionally active human interferon-γ (IFNγ) receptors require the presence of at least two polypeptides: the IFNγ receptor and an accessory molecule encoded by a gene on human chromosome 21. Here we have used a murine L cell line that stably contains human chromosome 21 (SCC16-5) to determine whether the receptor's cytoplasmic domain is important for receptor function. SCC16-5 stably transfected with the full-length human IFNγ receptor cDNA bound, internalized, and responded to human IFNγ. In contrast, SCC16-5 expressing human IFNγ receptors lacking a cytoplasmic domain bound human IFNγ but did not internalize or respond to it. Using a family of IFNγ receptor deletion mutants, two functionally important regions within the intracellular domain were identified: (a) a membrane proximal region (residues 256-303) required for ligand processing and biologic responsiveness and (b) the carboxyl-terminal 39 amino acids (residues 434-472) needed exclusively for biologic responses.