IFN-γ: An Intracellular Ligand?

Science's STKE  01 Jul 2003:
Vol. 2003, Issue 189, pp. tw250-TW250
DOI: 10.1126/stke.2003.189.tw250

Interferon-γ (IFN-γ) is a cytokine involved in antiviral responses. Cells exposed to IFN-γ that also express its receptor, which consists of IFNGR1 and IFNGR2, activate a signaling cascade that stimulates the phosphorylation and nuclear translocation of STATs (signal transducers and activators of transcription). Ahmed et al. provide evidence that IFN-γ can stimulate phosphorylation and nuclear translocation of STAT1α by interacting with the intracellular domain of the IFNGR1. When expressed in mouse L cells, which cannot bind human IFN-γ through an extracellular domain of the murine IFN receptor, a version of human IFN-γ that is not secreted promoted cell survival in response to viral challenge, stimulated surface expression of major histocompatibility complex type I receptors, and stimulated production of phosphorylated STAT (p-STAT). A version of nonsecreted IFN-γ that lacked a functional nuclear localization sequence (NLS) increased p-STAT, but none of the other responses. Immunoprecipitation assays showed that intracellular IFN-γ formed a complex with IFNGR1, p-STAT, and the nuclear importin homolog NPI-1. The authors showed that extracellularly applied IFN-γ was internalized, bound to a cytoplasmic domain of the receptor, and stimulated p-STAT formation. An IFNGR1 intracellular domain peptide blocked binding and stimulation of p-STAT. A C-terminal deletion mutant of IFN-γ that lacked the NLS did not bind the intracellular domain of IFNGR1. The authors propose that IFN-γ has two modes of action: one that is the result of binding to the extracellular domain of the IFN receptor and one that is the result of binding to the intracellular domain of the IFN receptor following internalization of the receptor-ligand complex. Both of these activities converge on activation of STATs to regulate gene expression.

C. M. I. Ahmed, M. A. Burkhart, M. G. Mujtaba, P. S. Subramaniam, H. M. Johnson, The role of IFNγ nuclear localization sequence in intracellular function. J. Cell Sci. 116, 3089-3098 (2003). [Abstract] [Full Text]