The structure and function of interferon-gamma receptors.
Interferon-gamma exerts its pleiotropic immunomodulatory effects by interacting with a single type of IFN gamma receptor expressed on nearly all cells. Human and murine IFN gamma receptors have been purified, their cDNAs cloned and expressed, and their primary structure elucidated. In addition, a considerable amount of data is available that defines the life cycle of the receptor including the kinetics of its biosynthesis, its constitutive- and ligand-induced phosphorylation, and its recycling behavior. Recent transfection experiments have revealed that an additional species-specific component is necessary to form functionally active IFN gamma receptors in heterologous cells. On the basis of complementation assays, the gene for the human accessory molecule has been localized to human chromosome 21. However, the nature of the gene product(s) remains unknown. Using murine fibroblasts that contain a single copy of human chromosome 21 and eukaryotic cell expression vectors that contain a series of human IFN gamma receptor intracellular domain deletion mutants, we have been able to demonstrate that the receptor's intracellular domain plays an obligatory role in mediating IFN gamma-dependent biologic responses. Subsequent studies showed that two distinct regions of the intracellular domain are functionally important: a membrane proximal region of 48 amino acids needed for both internalization and induction of biologic responses and the carboxy terminal 39 amino acids needed only for function and not for internalization. Moreover, receptor-mediated ligand internalization was found to be insufficient for biologic response induction.(ABSTRACT TRUNCATED AT 250 WORDS)
Schreiber
R D
RD
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110.
Farrar
M A
MA
Hershey
G K
GK
Fernandez-Luna
J
J
D000818:Animals; D002891:Chromosomes, Human, Pair 21; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017471:Receptors, Interferon; D013329:Structure-Activity Relationship
D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D007371:Interferon-gamma