Mechanisms of Jak/STAT Signaling in Immunity and Disease Alejandro V. Villarino, Yuka Kanno, John R. Ferdinand and John J. O'Shea This information is current as of October 2, 2021. J Immunol 2015; 194:21-27; ; doi: 10.4049/jimmunol.1401867 http://www.jimmunol.org/content/194/1/21 Downloaded from References This article cites 73 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/1/21.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Mechanisms of Jak/STAT Signaling in Immunity and Disease Alejandro V. Villarino, Yuka Kanno, John R. Ferdinand, and John J. O’Shea More than two decades ago, experiments on the antivi- Specificity and redundancy in Jak/STAT signaling ral mechanisms of IFNs led to the discovery of JAKs and The biochemistry of Jak/STAT signaling has been studied their downstream effectors, the STAT proteins. This extensively (2). Briefly, signaling begins with extracellular pathway has since become a paradigm for membrane- association of cytokines or growth factors with their corre- to-nucleus signaling and explains how a broad range sponding transmembrane receptors. This facilitates trans-ac- of soluble factors, including cytokines and hormones, tivation of receptor-bound Jaks by putting them in spatial mediate their diverse functions. Jak/STAT research proximity and by prompting conformational changes that has not only impacted basic science, particularly in the distance their kinase domains from inhibitory pseudokinase Downloaded from context of intercellular communication and cell-extrinsic domains (3). Activated Jaks then phosphorylate latent STAT control of gene expression, it also has become a proto- monomers, leading to dimerization, nuclear translocation, type for transition from bench to bedside, culminating and DNA binding (Fig. 1). In mammals, four Jaks (JAK1, in the development and clinical implementation of JAK2, JAK3, TYK2) and seven STATs (STAT1, STAT2, pathway-specific therapeutics. This brief review synthe- STAT3, STAT4, STAT5a, STAT5b, STAT6) are used by . sizes our current understanding of Jak/STAT biology 50 cytokines and growth factors, raising the question of http://www.jimmunol.org/ while taking stock of the lessons learned and the chal- how specificity is achieved with so few building blocks. One lenges that lie ahead. The Journal of Immunology, explanation is that specificity is lineage dependent, meaning 2015, 194: 21–27. that cytokines that activate the same STATs may operate on different cell types (or states), each with distinct panels of STAT-sensitive genes. However, this does not explain why etazoans, and even unicellular aggregates, must cytokines that “look” similar in terms of STAT-signaling coordinate the diverse activities of cellular hordes cascades can have different outcomes within the same cell to achieve collective goals. This imperative underlies type or state. A classic example of this dichotomy is the case of M by guest on October 2, 2021 two fundamental questions in biology: how do individual IL-6 and IL-10; both are potent STAT3 activators in myeloid cells sense external cues and, in turn, how are these external cells, but the former exerts mostly proinflammatory effects, cues interpreted to program behavior? Evolution has provided whereas the latter is mostly anti-inflammatory. There is evi- a number of elegant solutions; among these, the Jak/STAT dence that qualitative differences in the duration and or in- pathway has emerged as a paradigm, as evidenced by its con- tensity of STAT3 signaling underlie the disparity, but this servation across phylogeny from vertebrates to lower organ- may not be the whole story (4). Another point to consider is isms like Dictyostelium (1). Not surprisingly, the study of that, although each cytokine is traditionally associated with this ancient pathway has yielded fundamental insights about a particular STAT, almost all engage more than one family cellular communication and the role of membrane-to- member to varying degrees (i.e., heterogeneous signaling; nucleus signaling in controlling gene expression. It also has Fig. 1). For example, type I IFNs are prototypical STAT1 shaped our understanding of the mammalian immune sys- activators but also activate STAT3 and STAT4 (5). In some tem, perhaps the most intricate of all cellular networks, and instances, cytokines engage multiple STATs with comparable provided both the impetus and rationale for pathway- potency, as with IL-27, a strong activator of both STAT1 and specific therapeutics. This brief review discusses current STAT3 (6), whereas in others there is clear hierarchy, as with theories on how Jak/STAT signaling works at the cellular, IFN-g, which elicits a strong STAT1 response coupled to molecular, and genomic levels, with particular emphasis a relatively weak STAT3 response (7). This heterogeneity is on human disease. Our aim is not to be expansive but, philosophically satisfying because graded combinations of rather, to highlight emerging ideas and to present a modern STATs may contribute to cytokine specificity, although it is view of Jak/STAT research as it strides forward into its third also unlikely that such quantitative differences account for all decade. of it. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Mus- Skin Diseases, National Institutes of Health, Building 10, Room 13C103C, 10 Center culoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 Drive, Bethesda, MD 20892. E-mail address: [email protected] Received for publication July 30, 2014. Accepted for publication September 25, 2014. Abbreviations used in this article: GAS, IFN-g activation site; GWAS, genome-wide association study; lncRNA, long noncoding RNA; miRNA, microRNA; SNP, single Address correspondence and reprint requests to Dr. John J. O’Shea, Molecular Immu- nucleotide polymorphism; TF, transcription factor. nology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401867 22 BRIEF REVIEWS: MECHANISMS OF JAK/STAT SIGNALING Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 FIGURE 1. Canonical Jak/STAT signaling begins with the association of cytokines and their corresponding transmembrane receptors. This brings Jaks in proximity, leading to phosphorylation of both the Jaks themselves and the cytoplasmic tails of the receptors, creating requisite docking sites for latent STAT monomers. STAT p-Tyr then proceeds as the major activating event, leading to dimerization, translocation, DNA binding, and target gene induction. Noncanonical deviations from this model also should be considered. First, p-Tyr can occur via Jak-independent pathways and, in fact, is not required for some activities (unphosphorylated STATs). Additional posttranslational modifications (e.g., p-Ser) also can influence STATs. Next, although each cytokine/receptor is typically associated with a particular STAT, most engage more than one family member (heterogeneous signaling), leading to the formation of homodimers, as wellas heterodimers and higher-order tetramers. These migrate to the nucleus where they bind to DNA through consensus GAS elements, as well as through GAS- independent mechanisms, leading to induction, repression, or neutral binding of protein-coding (mRNAs) or noncoding (miRNAs and lncRNAs) target genes, typically as part of multimolecular complexes. Because of a shared affinity for GAS motifs, multiple STATs may bind to the same target sites (overlapping specificities). They also can bind to and promote remodeling of gene enhancers and regulate the epigenetic status of target genes. Lastly, extranuclear functions have increasingly been recognized, most notably in the mitochondrion. It is well established that STATs can bind directly to DNA, Genome-wide analyses have yielded a number of surprises thus acting as classical transcription factors (TFs). Exactly where about STAT biology. First is the pervasive nature of STAT and how they bind are matters of ongoing debate. Traditionally, binding. In Th cells, thousands of binding sites have been these questions have been addressed using low-throughput, mapped for each family member, sometimes proximal to candidate-driven approaches but, with the advent of next- transcriptional start sites, as would have been predicted, but generation sequencing, it is now possible to tackle them on a more often distal, typically associated with enhancers or other genome-wide scale. Most notably, deep sequencing can be cis-regulatory elements (10). Many of these binding events are coupled with chromatin immunoprecipitation to produce com- not associated with consensus DNA motifs (i.e.,