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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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
Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F
Rajintha M Bandaranayake,Daniela Ungureanu,Yibing Shan,David E. Shaw,David E. Shaw,Olli Silvennoinen,Stevan R. Hubbard +6 more
TL;DR: The structures reveal that JH2 adopts the fold of a prototypical protein kinase but binds Mg-ATP noncanonically, and the structural and biochemical data indicate that the V617F mutation rigidifies α-helix C in the N lobe ofJH2, facilitating trans-phosphorylation of JH1.
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The Signal Transducer STAT5 Inhibits Plasmacytoid Dendritic Cell Development by Suppressing Transcription Factor IRF8
Eiji Esashi,Yui-Hsi Wang,Olivia A. Perng,Xiao Feng Qin,Xiao Feng Qin,Yong-Jun Liu,Yong-Jun Liu,Stephanie S. Watowich,Stephanie S. Watowich +8 more
TL;DR: The results show that GM-CSF controls the production of pDCs by employing STAT5 to suppress IRF8 and the pDC transcriptional network in lin- Flt3+ progenitors.
Journal ArticleDOI
Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells
TL;DR: Opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection are revealed.
Journal ArticleDOI
Insights into Cytokine–Receptor Interactions from Cytokine Engineering
TL;DR: The theory and practice of cytokine engineering is reviewed and the mechanisms of several engineered cytokines are rationalized in the context of structure, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleokin-4.
Journal ArticleDOI
SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production
Reiko Takahashi,Shuhei Nishimoto,Go Muto,Takashi Sekiya,Taiga Tamiya,Akihiro Kimura,Rimpei Morita,Mayako Asakawa,Takatoshi Chinen,Akihiko Yoshimura +9 more
TL;DR: SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells.