Inteferons pen the JAK-STAT pathway

Abstract

Characterization of how interferons (IFNs) mediate their biological response led to identification of the JAK-STAT signaling cascade, where JAKs are receptor-associated kinases and STATs the transcription factors they activate. Today, 4 JAKs and 7 STATs are known to transduce pivotal signals for the over 50 members of the four-helix bundle family of cytokines. This review will provide an overview and historical perspective of the JAK-STAT paradigm.

Figure 1. Structural organization of the JAK and STAT families

The JAKs share seven JAK homology (JH) domains, JH1-JH7. JH1 serves as the catalytic domain, whereas JH2 represents a pseudokinase domain. JH4 includes an SH2-like domain of unknown function and JH4-JH7 comprise a FERM domain that is responsible for association with cytokine receptors. The six STATs share 7 functionally conserved domains. They include the amino terminal domain (NH₂), the coiled-coiled domain (Coiled-Coil), the DNA binding domain (DBD), the Linker domain (LK), the SH2 domain, the tyrosine activation domain, and the transcriptional activation domain (TAD).

Figure 2. The IFN-I and IFN-γ signaling paradigm

Upon binding to its dimeric receptor (IFNAR1 & IFNAR2), type I IFN promotes the apposition of two receptor associated JAKs (Jak1 & Tyk2), directing transphosphorylation and activation. The activated JAKs then phosphorylate receptor tyrosine(s), promoting a SH2 domain dependent recruitment of Stat1 and Stat2. At the receptor, Stat1 and Stat2 are activated by phosphorylation, they heterodimerizes, translocate into the nucleus, and associate with IRF-9 to from ISGF-3, which binds to ISREs to drive the expression of corresponding target genes. Only type I and type III IFNs signal through this pathway. IFN-γ directs the activation of a unique dimeric receptor (i.e., IFNGR1 & IFNGR2) by promoting the activation of two receptor associated JAKs (i.e., Jak1 and Jak2). These JAKs phosphorylate a single IFNGR1 tyrosine, which directs the SH2 domain dependent recruitment and activation of Stat1. Activated Stat1 homodimers translocate to the nucleus, bind to the members of the GAS family of enhancers and drive the expression of target genes. All four-helix bundle cytokines family, including type I and III IFNs transduce signals through this pathway.