Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Abstract

Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs.

Figure 1.

Outline of Janus kinase–signal transducers and activators of transcription (JAK-STAT) signaling shows that interferon (IFN)-γ (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-β and the subtypes of IFN-α (collectively type I IFNs), and the subtypes of IFN-λ (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form interferon-stimulated gene factor 3 (ISGF3). Also shown are STAT transcription factors that form and function without tyrosine phosphorylation (unphosphorylated STATs [U-STATs]).