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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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
Heterodimeric JAK-STAT Activation As a Mechanism of Persistence to JAK2 Inhibitor Therapy
Neha Bhagwat,Priya Koppikar,Outi Kilpivaara,Taghi Manshouri,Mazhar Adli,Ann Mullally,Omar Abdel-Wahab,Laura Leung,Abby R. Weinstein,Sachie Marubayashi,Aviva Goel,Mithat Gonen,Zeev Estrov,Benjamin L. Ebert,Gabriela Chiosis,Bradley E. Bernstein,Srdan Verstovsek,Ross L. Levine +17 more
TL;DR: The data and the clinical experience suggest that the failure of JAK2 inhibitors to reduce disease burden is not due to acquired drug resistance but rather due to persistent growth and signaling in the setting of chronic Jak2 kinase inhibition.
Journal ArticleDOI
The STAT5b Pathway Defect and Autoimmunity.
TL;DR: The likely pathophysiological mechanisms associated with STAT5b deficiency are reviewed, including immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, γ−δ T cells, and natural killer (NK) cells.
Journal ArticleDOI
Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells
Chi-Keung Wan,Allison B. Andraski,Rosanne Spolski,Peng Li,Majid Kazemian,Jangsuk Oh,Leigh Samsel,Phillip A. Swanson,Dorian B. McGavern,Elizabeth P. Sampaio,Alexandra F. Freeman,Joshua D. Milner,Steven M. Holland,Warren J. Leonard +13 more
TL;DR: IL-21–mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, aswell as in cells from STAT1 gain-of-function patients, suggesting an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.
Journal ArticleDOI
The Ligase PIAS1 Restricts Natural Regulatory T Cell Differentiation by Epigenetic Repression
TL;DR: It is reported here that the SUMO E3 ligase PIAS1 restricts the differentiation of natural Treg cells by maintaining a repressive chromatin state of the Foxp3 promoter.
Journal ArticleDOI
Defective IL-2-mediated IL-2 receptor alpha chain expression in Stat3-deficient T lymphocytes.
Hiroshi Akaishi,Kiyoshi Takeda,Tsuneyasu Kaisho,Ryuzaburo Shineha,Susumu Satomi,Junji Takeda,Shizuo Akira +6 more
TL;DR: It is demonstrated that Stat3 activation is required for efficient T cell proliferation by IL-2 throughIL-2Ralpha induction, which is responsible for IL-1- and IL-6-induced proliferation through distinct mechanisms.