Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

https://science.sciencemag.org/content/sci/264/5164/1415.full.pdf

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.

http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Biochemistry/Interferons.pdf

How cells respond to interferons

Dimerization of cell surface receptors in signal transduction

Summary: Recombinant interferon-α (IFN-α) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-α paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. This review summarizes the history of the purification of human IFNs and the key aspects of our current state of knowledge of human IFN genes, proteins, and receptors. All the known IFNs and IFN-like cytokines are described [IFN-α, IFN-β, IFN-e, IFN-κ, IFN-ω, IFN-δ, IFN-τ, IFN-γ, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29] as well as their receptors and signal transduction pathways. The biological activities and clinical applications of the proteins are discussed. An extensive section on the evolution of these molecules provides some new insights into the development of these proteins as major elements of innate immunity. The overall structure of the IFNs is put into perspective in relation to their receptors and functions.

Interferons, interferon‐like cytokines, and their receptors

BACKGROUND

Genetic differences in immune responses may affect susceptibility to mycobacterial infection, but no specific genes have been implicated in humans. We studied four children who had an unexplained genetic susceptibility to mycobacterial infection and who appeared to have inherited the same recessive mutation from a common ancestor.

METHODS

We used microsatellite analysis, immunofluorescence studies, and sequence analysis to study the affected patients, unaffected family members, and normal controls.

RESULTS

A genome search using microsatellite markers identified a region on chromosome 6q in which the affected children were all homozygous for eight markers. The gene for interferon-gamma receptor 1 maps to this region. Immunofluorescence studies showed that the receptor was absent on leukocytes from the affected children. Sequence analysis of complementary DNA for the gene for interferon-gamma receptor 1 revealed a point mutation at nucleotide 395 that introduces a stop codon and results in a truncated protein that lacks the transmembrane and cytoplasmic domains.

CONCLUSIONS

Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma. The interferon-gamma pathway is important in the response to intracellular pathogens such as mycobacteria.

https://www.nejm.org/doi/pdf/10.1056/NEJM199612263352602

A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.

https://www.cell.com/cell/pdf/0092-8674(94)90354-9.pdf

Toru Miki

Papers

Identification and sequence of an accessory factor required for activation of the human interferon γ receptor

Differential Requirement for Rho Family GTPases in an Oncogenic Insulin-like Growth Factor-I Receptor-induced Cell Transformation