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.
TL;DR: Tocilizumab is a blocker of IL-6R, which can effectively block IL- 6 signal transduction pathway, and is likely to become an effective drug for patients with severe COVID-19.
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Kinase inhibitors: the road ahead
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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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Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
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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
Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing
Dan R. Robinson,Yi-Mi Wu,Shanker Kalyana-Sundaram,Shanker Kalyana-Sundaram,Xuhong Cao,Robert J. Lonigro,Yun Shao Sung,Chun-Liang Chen,Lei Zhang,Rui Wang,Fengyun Su,Matthew K. Iyer,Sameek Roychowdhury,Javed Siddiqui,Kenneth J. Pienta,Lakshmi P. Kunju,Moshe Talpaz,Juan Miguel Mosquera,Samuel Singer,Scott M. Schuetze,Cristina R. Antonescu,Arul M. Chinnaiyan +21 more
TL;DR: These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into an transcriptional activator.
Journal ArticleDOI
Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB
TL;DR: U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT2, and is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P- STAT3.
Journal ArticleDOI
Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5.
Xiang-Ping Yang,Kamran Ghoreschi,Scott M. Steward-Tharp,Jaime Rodriguez-Canales,Jinfang Zhu,John R. Grainger,Kiyoshi Hirahara,Hong-Wei Sun,Lai Wei,Golnaz Vahedi,Yuka Kanno,John J. O'Shea,Arian Laurence +12 more
TL;DR: Deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency and 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL- 17-producing helper T cell (TH17 cell) subset.
Journal ArticleDOI
Nonredundant roles for Stat5a/b in directly regulating Foxp3
Zhengju Yao,Zhengju Yao,Yuka Kanno,Marc A. Kerenyi,Geoffrey L. Stephens,Lydia Durant,Wendy T. Watford,Arian Laurence,Gertraud W. Robinson,Ethan M. Shevach,Richard Moriggl,Lothar Hennighausen,Chang-You Wu,John J. O'Shea +13 more
TL;DR: It is concluded that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5 a/b appear to have opposing roles in the regulation of Foxp3.
Journal ArticleDOI
Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue
Jeroen P. J. Saeij,S. Coller,Jon P. Boyle,Maria E. Jerome,Michael W. White,John C. Boothroyd +5 more
TL;DR: This work uses genetic crosses between type II and III lines to show that strain-specific differences in the modulation of host cell transcription are mediated by a putative protein kinase, ROP16, and provides a new mechanism for how an intracellular eukaryotic pathogen can interact with its host.