Journal ArticleDOI
Mechanisms and consequences of Jak–STAT signaling in the immune system
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TLDR
Recent advances in Jak–STAT biology are reviewed, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.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.read more
Citations
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Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality.
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IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy.
TL;DR: This Review focuses on recent advances in the understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an ‘M1-like’ state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors.
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Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens
Atray Dixit,Atray Dixit,Oren Parnas,Biyu Li,Jenny Chen,Jenny Chen,Charles P. Fulco,Charles P. Fulco,Livnat Jerby-Arnon,Nemanja D. Marjanovic,Nemanja D. Marjanovic,Danielle Dionne,Tyler Burks,Raktima Raychowdhury,Britt Adamson,Thomas M. Norman,Eric S. Lander,Eric S. Lander,Eric S. Lander,Jonathan S. Weissman,Jonathan S. Weissman,Nir Friedman,Nir Friedman,Aviv Regev,Aviv Regev,Aviv Regev +25 more
TL;DR: Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions, and posit new functions for regulators of differentiation, the anti-viral response, and mitochondrial function during immune activation.
References
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Journal ArticleDOI
TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes.
Anna Yarilina,Kyung-Hyun Park-Min,Taras T. Antoniv,Xiaoyu Hu,Lionel B. Ivashkiv,Lionel B. Ivashkiv +5 more
TL;DR: Investigation of the kinetics of primary macrophage responses to TNF discovered that TNF initiates an interferon-β-mediated autocrine loop that sustains expression of inflammatory genes and induces delayed expression of interFERon-response genes such as those encoding the transcription factors STAT1 and IRF7, which enhance macrophages responses to stimulation of cytokines and Toll-like receptors.
Journal ArticleDOI
Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins.
Susan A. Veals,Chris Schindler,Debra G.B. Leonard,Xin-Yuan Fu,Ruedi Aebersold,James E. Darnell,David E. Levy +6 more
TL;DR: Sequencing of ISGF3 gamma cDNA clones revealed significant similarity to the interferon regulatory factor (IRF) family of DNA binding proteins in the amino-terminal 117 residues of IS GF3 gamma, suggesting that other IRF family members may participate in signaling pathways by interacting with as yet unidentified regulatory subunits analogous toISGF3 alpha.
Journal ArticleDOI
Regulation of Interferon-γ-Activated STAT1 by the Ubiquitin-Proteasome Pathway
Tae Kook Kim,Tom Maniatis +1 more
TL;DR: STAT1 proteins activated by interferon-γ treatment in HeLa cells were shown to be stabilized by a proteasome inhibitor and ubiquitinated in vivo, suggesting the amount of activated STAT1 may be negatively regulated by the ubiquitin-proteasome pathway.
Journal Article
Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Commentary
Ross L. Levine,Ralph Tiedt,Hui Hao-Shen,Marta Anna Sobas,Renate Looser,Stephan Dirnhofer,Jürg Schwaller,Radek C. Skoda +7 more
TL;DR: In this article, the authors generated JAK2-V617F transgenic mice with the sequences encoding the kinase domain placed in the inverse orientation and flanked by antiparallel loxP sites.
Journal ArticleDOI
A Critical Role for Stat3 Signaling in Immune Tolerance
Fengdong Cheng,Hongwei Wang,Alex G. Cuenca,Mei Huang,Tomar Ghansah,Jason Brayer,William G. Kerr,Kiyoshi Takeda,Shizuo Akira,Stephen P. Schoenberger,Hua Yu,Richard Jove,Eduardo M. Sotomayor +12 more
TL;DR: It is shown that Stat3 signaling plays a critical role in the induction of antigen-specific T cell tolerance, and provides a novel molecular target for manipulation of immune activation/tolerance, a central decision with profound implications in autoimmunity, transplantation, and cancer immunotherapy.