Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses

Abstract

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK-STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1.

Keywords: JAK–STAT; innate immunity; interferon; non-canonical; signal transduction.

Figure 1

Canonical and non-canonical STAT signaling by the IFN receptors. Proposed roles of STAT or STAT/interferon regulatory factor (IRF9) complexes participating in signal transduction and transcriptional activation by the receptors of IFN-I, IFN-II or IFN-III. Complexes containing IRF9 associate with interferon-stimulated response elements promoter sequences whereas dimerized STAT1 binds to GAS elements.

Figure 2

Levels of unphosphorylated signal transducer and activator of transcriptions (STATs) determine the strength of responses to type I IFN and IFNγ. The model is based on work published in references 99 and 118 showing that unphosphorylated STAT1 binds to tyrosine-phosphorylated STAT2 and vice versa. Such hemiphosphorylated STAT dimers are incapable of nuclear translocation (118). In the IFNγ response, unphosphorylated STAT2 thus lowers the formation and nuclear translocation of tyrosine-phoshorylated STAT1 dimers (118). Conversely, unphosphorylated STAT1 inhibits the nuclear translocation of tyrosine-phosphorylated STAT2 in the type I IFN response (99).

Figure 3

U-STAT signaling in the type I IFN response. Early canonical signaling causes the upregulation of IFN-stimulated gene factor 3 (ISGF3) subunits and the subsequent formation of an ISGF3 complex with unphosphorylated signal transducer and activator of transcriptions 1 and 2 [unphosphorylated ISGF3 complex (U-ISGF3)]. U-ISGF3 stimulates a subset of interferon-stimulated genes to prolong the transcriptional response to IFN-I.