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.
T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior, and/or differentiation state. Many of these adaptations are controlled by ...cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K‐AKT, mTOR, or ERK‐MAPK pathways but recent studies indicate that JAK‐STAT is also crucial. This review synthesizes current thinking on how JAK‐STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory, and resident‐memory states. The overarching theme is that JAK‐STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism‐related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non‐canonical JAK‐STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid, and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK‐STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands.
STAT family transcription factors instruct both anabolic and catabolic metabolism in T cells. STAT3 signaling typically supports catabolic metabolism, specifically Fatty Acid Oxidation (FAO), glutaminolysis, and Oxidative Phosphorylation (OxPhos). STAT5 signaling typically supports both catabolic and anabolic metabolism, including FAO, glycolysis glutaminolysis, OxPhos and fatty, amino, and nucleotide acid synthesis.
A “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why ...proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-γ is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3′ UTR of IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function.
Display omitted
Display omitted
•T cells do not require aerobic glycolysis to fuel proliferation or survival•Glycolysis is specifically required for effector cytokine production in T cells•When not engaged in glycolysis, GAPDH binds to cytokine mRNA•Changes in available GAPDH regulate cytokine mRNA translation
Contrary to previous understanding, activated T cells switch from oxidative phosphorylation to aerobic glycolysis not to promote proliferation but instead to augment the production of the antimicrobial protein IFN-γ, which is regulated by the glycolytic enzyme GAPDH.
Mechanisms of Jak/STAT signaling in immunity and disease Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R ...
The Journal of immunology (1950),
2015-Jan-01, 2015-01-01, 20150101, Letnik:
194, Številka:
1
Journal Article
Recenzirano
Odprti dostop
More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for ...membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.
The Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, ...growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs.
Interleukin-6 (IL-6) and IL-27 signal through a shared receptor subunit and employ the same downstream STAT transcription proteins, but yet are ascribed unique and overlapping functions. To evaluate ...the specificity and redundancy for these cytokines, we quantified their global transcriptomic changes and determined the relative contributions of STAT1 and STAT3 using genetic models and chromatin immunoprecipitation-sequencing (ChIP-seq) approaches. We found an extensive overlap of the transcriptomes induced by IL-6 and IL-27 and few examples in which the cytokines acted in opposition. Using STAT-deficient cells and T cells from patients with gain-of-function STAT1 mutations, we demonstrated that STAT3 is responsible for the overall transcriptional output driven by both cytokines, whereas STAT1 is the principal driver of specificity. STAT1 cannot compensate in the absence of STAT3 and, in fact, much of STAT1 binding to chromatin is STAT3 dependent. Thus, STAT1 shapes the specific cytokine signature superimposed upon STAT3’s action.
Display omitted
•The transcriptomic output driven by IL-6 or IL-27 is primarily regulated by STAT3•STAT1 does not compensate for STAT3 to drive transcriptional output•Much of STAT1 binding to chromatin is STAT3-dependent•The ability to access STAT1 magnifies the difference between IL-6 and IL-27
Interleukin-6 (IL-6) and IL-27 are ascribed unique and overlapping functions while sharing a receptor subunit and downstream STAT. Using genomic approaches, O’Shea and colleagues report that STAT3 is responsible for transcriptomic output, whereas STAT1 regulates cytokine specificity.
Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, ...we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
Display omitted
•Non-classical MHC class I molecules promote homeostatic immunity to the microbiota•Commensal-specific T cells express immunoregulatory and tissue repair signatures•Commensal-specific T cells accelerate wound closure
Microbiota induce a form of adaptive immunity that couples antimicrobial function with tissue repair.
SnapShot: Jak-STAT Signaling II Villarino, Alejandro V.; Gadina, Massimo; O’Shea, John J. ...
Cell,
06/2020, Letnik:
181, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The JAK-STAT pathway is an evolutionarily conserved signal transduction paradigm, providing mechanisms for rapid receptor-to-nucleus communication and transcription control. Discoveries in this field ...provided insights into primary immunodeficiencies, inherited autoimmune and autoinflammatory diseases, and hematologic and oncologic disorders, giving rise to a new class of drugs, JAK inhibitors (or Jakinibs).
Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The ...discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate ...lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response.
Display omitted
•Inducible high-density p300 enhancers form in proximity to highly dynamic genes•Strong transcriptional induction occurs with both primed and non-primed enhancers•De novo enhancers form in vivo during NK cell response to Toxoplasma gondii infection•STATs initiate chromatin opening with T-bet redeployment to non-canonical sites
During development, innate lymphocytes acquire defined sets of primed enhancers facilitating the rapid immune response. In this issue of Immunity, Sciumè et al. delineate the epigenetic changes occurring during acute NK cell activation, revealing the formation of de novo enhancers and repurposing of both lineage-determining and signal-regulated transcription factors.
PDF
