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.
Journal ArticleDOI
Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
TL;DR: The key roles of the IL-6 cytokine family in regulating innate and adaptive immunity, as well as other physiological responses are considered, which highlight the potential of targeting IL- 6 family members to treat inflammatory diseases and cancer.
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
The IL-27R (WSX-1) Is Required to Suppress T Cell Hyperactivity during Infection
Alejandro V. Villarino,Linda Hibbert,Linda A. Lieberman,Emma H. Wilson,Tak W. Mak,Hiroki Yoshida,Hiroki Yoshida,Robert A. Kastelein,Christiaan J. M. Saris,Christopher A. Hunter +9 more
TL;DR: It is demonstrated that WSX-1 is not required for the generation of IFN-gamma-mediated immunity to this parasitic infection and a novel function for this receptor is identified as a potent antagonist of T cell-mediated, immune hyperactivity.
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Cooperative DNA Binding and Sequence-Selective Recognition Conferred by the STAT Amino-Terminal Domain
Xiang Xu,Ya-Lin Sun,Timothy Hoey +2 more
TL;DR: The transcriptional specificity of STAT proteins was investigated on natural STAT binding sites near the interferon-gamma gene, where the conserved amino-terminal domain was required for cooperative DNA binding, although this domain was not essential for dimerization or binding to a single site.
Journal ArticleDOI
Whole exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors
Juliann Chmielecki,Aimee M. Crago,Mara Rosenberg,Rachael O'Connor,Sarah R. Walker,Sarah R. Walker,Lauren Ambrogio,Daniel Auclair,Aaron McKenna,Michael Heinrich,David A. Frank,David A. Frank,Matthew Meyerson,Matthew Meyerson +13 more
TL;DR: Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors, representing a lower bound for fusion frequency at this locus and suggesting that the NAB2-STAT6 fusion is a distinct molecular feature of SFTs.
Journal ArticleDOI
STAT5 is a potent negative regulator of TFH cell differentiation
Robert J. Johnston,Youn Soo Choi,Jeffrey A. Diamond,Jessica A. Yang,Shane Crotty,Shane Crotty +5 more
TL;DR: Interleukin 2, STAT5, and Blimp-1 work together to suppress differentiation of follicular helper T cells in mice to promote T-cell reprograming and down-regulation.
Journal ArticleDOI
Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity.
TL;DR: The results demonstrate that the specificity of STAT-directed transcription in response to particular cytokines or cytokine families depends in part on the spacing of half sites within the conserved response element sequence.