Mechanisms and consequences of Jak-STAT signaling in the immune system

Abstract

Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.

Figure 1:

The Canonical Jak-STAT Pathway. Canonical Jak/STAT signaling begins with the extracellular association between cytokines and their corresponding transmembrane receptors. Receptor oligomerization then precipitates trans-activation of Jaks which phosphorylate the cytoplasmic tails of the receptors to create requisite docking sites for latent STATs. That puts Jaks and STATs in spacial proximity, leading to STAT tyrosine phosphorylation, dimerization, nuclear translocation, DNA binding and, ultimately, gene transcription. STATs typically engage loci bearing the Interferon-Gamma Activated Sequence (GAS), with the exception of STAT2, which participates in a trimeric complex (STAT1/STAT2/IRF9) that engages the Interferon-Stimulated Response Element (ISRE). Mammalian Jaks are composed of 4 domains: (1) the FERM domain, which mediates interaction with upstream receptors and promotes kinase function, (2) the SH2-like domain, which mediates interaction with upstream receptors, (3) the pseudokinase domain, which limits unwarranted kinase activity, and (4) the kinase domain, which contains the tyrosine residues necessary for trans-activation and the catalytic elements necessary for tyrosine phosphorylation of receptors, Jaks and STATs. Mammalian STATs are composed of 7 domains: (1) the N-terminal domain, which is involved in protein-protein interactions, (2) the coiled-coil domain, which is involved in protein-protein interactions and contains nuclear localization signals, (3) the DNA-binding domain, which directly interfaces DNA and contains nuclear import/export signals, (4) the linker domain, which is structurally important and promotes transcriptional activity, (5) the SH2 domain, which mediates dimerization and interaction with upstream receptors, (6) the transactivation domain, which contains the phospho-tyrosine residues necessary for canonical signaling and, (7) the carboxy terminal domain, which contains phospho-serine residues that support both canonical and non-canonical functions.

Figure 2:

STATs as transcription factors. STATs are classical transcription factors (TFs) in that they engage DNA regulatory elements (DREs) bearing a particular sequence motif and thereby instruct transcription of nearby genes. However, many of these gene-proximal sites are not clearly linked to gene transcription (i.e. neutral binding). STATs also engage distal DREs and control enhancer activity and/or epigenetic status of associated genes, sometimes through physical interaction with histone acetyltransferases (HATs) like p300 or methyl transferases (MTs) like Ezh2, or instruct distal non-coding loci (i.e. miRNAs, lincRNAs). STAT-regulated DREs are often studded with multiple binding sites which tend to attract more than one family member (i.e. STAT overlap) and co-localize with those of other TFs, sometimes reflecting the inclusion of STATs within multi-TF complexes.

Figure 3:

Fine tuning Jak-STAT signaling. The Jak/STAT pathway is subject to multiple levels of regulation. (1) STATs induce transcription of SOCS proteins which, in turn, limit STAT activity via inhibitory interactions with receptors and Jaks. (2) Phosphatases hydrolyze key tyrosine residues necessary for signal transduction by receptors, Jaks and STATs. (3) PIAS proteins suppress STAT-driven gene transcription. (4) STATs control transcription of genes encoding receptors and TFs that influence STAT activity as well as (5) genes encoding the STATs themselves. (6) MicroRNAs and RNA-binding proteins (RBPs) influence STAT mRNA half-life and translation. (7) Post-translational modifications, including serine phosphorylation, lysine acetylation, lysine methylation and sumoylation promote or suppress STAT activity. (8) Ubiquitin ligases drive proteasomal degradation of STAT proteins.

Figure 4:

Therapeutic targeting of the Jak/STAT pathway. Numerous strategies have been developed to manipulate the Jak/STAT pathway. Those currently approved or undergoing clinical trials in the U.S. include: (1) recombinant and engineered cytokines, (2) cytokine blocking antibodies (Ab), (3) receptor blocking antibodies, (4) agonists cytokine-Ab complexes, (5) agonists cytokine-Ab fusions (6), small molecule Jak inhibitors (Jakinibs), (7) small molecule RTK inhibitors, (8) STAT-binding inhibitory peptides, (9) small molecule STAT inhibitors, (10) STAT-targeting siRNAs, and (11) STAT-binding decoy oligonucleotides.