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.
Journal ArticleDOI
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
CDK8 Kinase Phosphorylates Transcription Factor STAT1 to Selectively Regulate the Interferon Response
Joanna Bancerek,Zachary C. Poss,Iris Steinparzer,Vitaly Sedlyarov,Thaddäus Pfaffenwimmer,Ivana Mikulic,Lars Dölken,Birgit Strobl,Mathias Müller,Dylan J. Taatjes,Pavel Kovarik +10 more
TL;DR: It is shown that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway, suggesting a general role for CDK8 in STAT-mediated transcription.
Journal ArticleDOI
Parsing the Interferon Transcriptional Network and Its Disease Associations
Sara Mostafavi,Sara Mostafavi,Hideyuki Yoshida,Devapregasan Moodley,Hugo LeBoité,Katherine Rothamel,Towfique Raj,Towfique Raj,Chun Jimmie Ye,Nicolas Chevrier,Shen-Ying Zhang,Ting Feng,Mark Lee,Jean-Laurent Casanova,James D. Clark,Martin Hegen,Jean-Baptiste Telliez,Nir Hacohen,Philip L. De Jager,Philip L. De Jager,Aviv Regev,Diane Mathis,Christophe Benoist +22 more
TL;DR: This paper performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages and distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration.
Journal ArticleDOI
The Significance of Tetramerization in Promoter Recruitment by Stat5
TL;DR: It is demonstrated that a dimeric but tetramerization-deficient Stat5 protein can activate only a subset of target sites, and for functional activity on a wider range of potential recognition sites, N-domain-mediated oligomerization is essential.
Journal ArticleDOI
Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6.
TL;DR: It is demonstrated in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosin residue for STAT6 activation, Tyr641, and taken together, these data strongly suggest that STAT6 is a direct substrate for Rop16 in vivo.
Journal ArticleDOI
Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection
Xiaohuan Guo,Ju Qiu,Tony Tu,Xuanming Yang,Liufu Deng,Robert A. Anders,Liang Zhou,Yang Xin Fu +7 more
TL;DR: Cancer therapies that utilize STAT3 inhibitors increase the risk for pathogen-mediated diarrhea through direct suppression of IL-22 from gut ILCs through directly binding to the Il22 locus.