The molecular basis for differential type I interferon signaling

J Biol Chem. 2017 May 5;292(18):7285-7294. doi: 10.1074/jbc.R116.774562. Epub 2017 Mar 13.


Type I interferons (IFN-1) are cytokines that affect the expression of thousands of genes, resulting in profound cellular changes. IFN-1 activates the cell by dimerizing its two-receptor chains, IFNAR1 and IFNAR2, which are expressed on all nucleated cells. Despite a similar mode of binding, the different IFN-1s activate a spectrum of activities. The causes for differential activation may stem from differences in IFN-1-binding affinity, duration of binding, number of surface receptors, induction of feedbacks, and cell type-specific variations. All together these will alter the signal that is transmitted from the extracellular domain inward. The intracellular domain binds, directly or indirectly, different effector proteins that transmit signals. The composition of effector molecules deviates between different cell types and tissues, inserting an additional level of complexity to the system. Moreover, IFN-1s do not act on their own, and clearly there is much cross-talk between the activated effector molecules by IFN-1 and other cytokines. The outcome generated by all of these factors (processing step) is an observed phenotype, which can be the transformation of the cell to an antiviral state, differentiation of the cell to a specific immune cell, senescence, apoptosis, and many more. IFN-1 activities can be divided into robust and tunable. Antiviral activity, which is stimulated by minute amounts of IFN-1 and is common to all cells, is termed robust. The other activities, which we term tunable, are cell type-specific and often require more stringent modes of activation. In this review, I summarize the current knowledge on the mode of activation and processing that is initiated by IFN-1, in perspective of the resulting phenotypes.

Keywords: STAT transcription factor; cell signaling; interferon; protein-protein interaction; receptor structure-function.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology*
  • Mice
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology*
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*


  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • Ifnar1 protein, mouse
  • Ifnar2 protein, mouse
  • Interferon-alpha
  • STAT Transcription Factors
  • Receptor, Interferon alpha-beta

Associated data

  • PDB/3SE3
  • PDB/3WCY
  • PDB/3S98
  • PDB/1N6U