Immunology
- cGAS‐STING do it again: pivotal role in RNase H2 genetic disease
RNase H2 is a susceptibility gene for the Aicardi–Goutières syndrome (AGS), a genetic auto‐inflammatory disease. Mackenzie and colleagues now report a tractable mouse model for the disease, implicating the cGAS‐STING pathway.
See also: KJ Mackenzie et al (April 2016)
A tractable new mouse model for Aicardi–Goutières syndrome (AGS) implicates the cGAS‐STING pathway for cytosolic nucleic acid sensing in this auto‐inflammatory disease.
- © 2016 The Authors
- USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin‐1
- Shouheng Jin1,2,†,
- Shuo Tian1,†,
- Yamei Chen1,†,
- Chuanxia Zhang2,
- Weihong Xie2,
- Xiaojun Xia3,4,
- Jun Cui*,1,3 and
- Rong‐Fu Wang*,5
- 1Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat‐sen University, Guangzhou, China
- 2Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, China
- 3Collaborative Innovation Center of Cancer Medicine, Sun Yat‐sen University, Guangzhou, China
- 4Department of Experimental Medicine, State Key Laboratory of Oncology in South China, Sun Yat‐sen University, Guangzhou, China
- 5Houston Methodist Research Institute, Houston, TX, USA
- ↵*
Corresponding author. Tel: +86 20 39943429; E‐mail: cuij5{at}mail.sysu.edu.cn
Corresponding author. Tel: +1 713 441 7359; E‐mail: rwang3{at}houstonmethodist.org
↵† These authors contributed equally to this work
USP19 stabilizes Beclin‐1 by cleaving K11‐linked ubiquitin chains on Beclin‐1, thereby promoting autophagy and inhibiting the type I IFN signaling pathway.
Synopsis
USP19 stabilizes Beclin‐1 by cleaving K11‐linked ubiquitin chains on Beclin‐1, thereby promoting autophagy and inhibiting the type I IFN signaling pathway.
USP19 facilitates autophagosome formation and functions as a new component of the Beclin‐1 complex.
USP19 rescues the proteasomal degradation of Beclin‐1 by removing K11‐linked ubiquitin chains at Lys437.
USP19 inhibits RIG‐I‐mediated type I IFN signaling as well as antiviral immune responses in a Beclin‐1‐dependent manner.
USP19‐Beclin‐1 blocks RIG‐I‐MAVS association, thereby suppressing type I IFN signaling.
The EMBO Journal (2016) 35: 866–880
- Received December 1, 2015.
- Revision received February 22, 2016.
- Accepted February 25, 2016.
- © 2016 The Authors
- The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6
- Dennis Stauss1,
- Cornelia Brunner2,
- Friederike Berberich‐Siebelt3,
- Uta E Höpken1,
- Martin Lipp1 and
- Gerd Müller*,1
- 1Department of Tumor Genetics and Immunogenetics, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
- 2Department of Physiological Chemistry, Department of Oto‐Rhino‐Laryngology Head and Neck Surgery, University of Ulm, Ulm, Germany
- 3Institute of Pathology, University of Würzburg, Würzburg, Germany
- ↵*Corresponding author. Tel: +49 30 9406 2836; E‐mail: g.mueller{at}mdc-berlin.de
Expression of the master Tfh cell differentiation factor Bcl6 is controlled by Bob1 and Oct1/2 transcription factors, to fine‐tune B‐cell responses following antigen‐mediated immunization.
Synopsis
Follicular T helper (Tfh) cells are essential for B cell‐mediated immunity. Tfh cell differentiation and the maintenance of the Tfh phenotype require continuous expression of high levels of Bcl6.
Bob1 enhances the expression of Bcl6 in CD4+ T cells, a master regulator of Tfh cell differentiation.
Bob1 is an important driver for the expression of B and T lymphocyte attenuator (BTLA, CD272) on Tfh cells.
Together with Oct1/2, Bob1 can directly bind to and transactivate the Bcl6 and Btla promoters.
Bob1 promotes Tfh cell differentiation and appears to fine‐tune the immune response following immunization with a protein antigen.
The EMBO Journal (2016) 35: 881–898
- Received March 6, 2015.
- Revision received November 18, 2015.
- Accepted January 8, 2016.
- © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response
- Karen J Mackenzie1,
- Paula Carroll1,
- Laura Lettice1,
- Žygimantė Tarnauskaitė1,
- Kaalak Reddy1,
- Flora Dix1,
- Ailsa Revuelta1,
- Erika Abbondati2,
- Rachel E Rigby1,3,
- Björn Rabe1,4,
- Fiona Kilanowski1,
- Graeme Grimes1,
- Adeline Fluteau1,
- Paul S Devenney1,
- Robert E Hill1,
- Martin AM Reijns1 and
- Andrew P Jackson*,1
- 1MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
- 2Roslin Institute, The University of Edinburgh, Edinburgh, UK
- 3MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC WIMM University of Oxford, Oxford, UK
- 4 Institute of Biochemistry, Christian‐Albrechts‐University of Kiel, Kiel, Germany
- ↵*Corresponding author. Tel: +44 131 651 8500; Fax: +44 131 467 8456; E‐mail: andrew.jackson{at}igmm.ed.ac.uk
A new mouse model reveals the key nucleic acid‐sensing and signalling pathway in autoinflammatory Aicardi–Goutières syndrome caused by RNase H2 mutations.
Synopsis
Mutations in the RNase H2 enzyme complex are the most frequent cause of the autoinflammatory condition Aicardi–Goutières syndrome (AGS). It is thought that nucleic acid sensing is responsible for initiating inflammation; however, the nature of the nucleic acid‐sensing pathway has not been determined. Here, we establish that:
Rnaseh2bA174T/A174T mice upregulate interferon‐stimulated genes (ISG) in tissues.
ISG response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING.
ISG induction is associated with reduced ribonucleotide excision repair (RER) activity and increased DNA damage.
The EMBO Journal (2016) 35: 831–844
- Received October 23, 2015.
- Revision received January 20, 2016.
- Accepted January 22, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Emancipation from transcriptional latency: unphosphorylated STAT5 as guardian of hematopoietic differentiation
- Thomas Decker (thomas.decker{at}univie.ac.at)1
The canonical paradigm of Jak‐STAT signaling is that members of the signal transducers and activators of transcription (STATs) family of transcription factors are activated by Janus kinase (Jak)‐mediated tyrosine phosphorylation. While the relationship between activation and tyrosine phosphorylation still appears axiomatic, several lines of evidence suggest that unactivated, unphosphorylated isoforms, uSTATs, are nonetheless also engaged in transcriptional regulation. In this issue of The EMBO Journal, Park et al (2015) make a convincing case that nuclear uSTAT5 controls hematopoietic differentiation.
See also: HJ Park et al (March 2016)
In canonical Jak–STAT signaling, Jak activates the transcription factor STAT by tyrosine phosphorylation. Now, unphosphorylated STAT5 is shown to directly repress transcription of a different set of target genes, mostly in proximity of CTCF sites, to control hematopoietic differentiation.
- © 2016 The Author. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Neutralization of pro‐inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis
- Liraz Shmuel‐Galia1,†,
- Tegest Aychek2,†,
- Avner Fink1,
- Ziv Porat3,
- Batya Zarmi1,
- Biana Bernshtein2,
- Ori Brenner4,
- Steffen Jung*,2 and
- Yechiel Shai*,1
- 1Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel
- 2Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
- 3Department of Biological Services, The Weizmann Institute of Science, Rehovot, Israel
- 4Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel
- ↵*
Corresponding author. Tel: +972 8 934 2787; Fax: +972 8 934 4141; E‐mail: s.jung{at}weizmann.ac.il
Corresponding author. Tel: +972 8 934 2711; Fax: +972 8 934 4112; E‐mail: yechiel.shai{at}weizmann.ac.il
↵† These authors contributed equally to the work
A novel approach for blocking TLR2 signaling modulates immune cell activation and reduces disease severity during acute gut inflammation.
Synopsis
Here, we utilize a novel strategy to neutralized TLR2 activation by inhibiting its dimerization by TLR2 transmembrane‐derived peptide (TLR2‐p). We show that TLR‐2 peptide ameliorated DSS‐induced colitis by interfering specifically with the activation of Ly6C+ monocytes without affecting their recruitment to the colon.
The TLR2 transmembrane‐derived peptide (TLR2‐p) inhibits TLR2 signaling by interacting with its reciprocal receptors within the membrane.
TLR2‐p inhibits the dimerization of TLR2–TLR6/1 induced by natural ligands, resulting in attenuation of pro‐inflammatory downstream signaling.
Inhibition of TLR2 dimerization ameliorates acute colitis.
TLR2‐p inhibits TLR2 signaling in pathogenic pro‐inflammatory Ly6Chi monocytes without affecting their recruitment to the inflamed gut.
The EMBO Journal (2016) 35: 685–698
- Received July 23, 2015.
- Revision received January 13, 2016.
- Accepted January 15, 2016.
- © 2016 The Authors
- p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
- Bárbara González‐Terán1,†,
- Nuria Matesanz1,†,
- Ivana Nikolic1,†,
- María Angeles Verdugo1,2,
- Vinatha Sreeramkumar1,
- Lourdes Hernández‐Cosido3,4,
- Alfonso Mora1,
- Georgiana Crainiciuc1,
- María Laura Sáiz1,
- Edgar Bernardo1,
- Luis Leiva‐Vega1,
- Elena Rodríguez1,
- Victor Bondía1,
- Jorge L Torres5,6,
- Sonia Perez‐Sieira7,8,
- Luis Ortega3,4,
- Ana Cuenda2,
- Francisco Sanchez‐Madrid1,
- Rubén Nogueiras7,8,
- Andrés Hidalgo1,
- Miguel Marcos5,6 and
- Guadalupe Sabio*,1
- 1Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
- 2Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
- 3Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain
- 4Department of Surgery, University of Salamanca, Salamanca, Spain
- 5Department of Internal Medicine, University Hospital of Salamanca‐IBSAL, Salamanca, Spain
- 6Department of Medicine, University of Salamanca, Salamanca, Spain
- 7Department of Physiology, CIMUS, University of Santiago de Compostela‐Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- 8CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- ↵*Corresponding author. Tel: +34 91453 12 00; E‐mail: guadalupe.sabio{at}cnic.es
↵† These authors contributed equally to this work
Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.
Synopsis
Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.
Expression of p38δ and p38γ is elevated in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).
p38γ/δ KO and myeloid‐specific p38γ/δ cKO mice are resistant to hepatic steatosis induced by high‐fat diet or methionine‐choline‐deficient diet.
p38γ/δ control neutrophil migration to the damaged liver.
Migration of neutrophils to the liver is necessary for the development of steatosis.
The EMBO Journal (2016) 35: 536–552
- Received April 20, 2015.
- Revision received December 18, 2015.
- Accepted December 22, 2015.
- © 2016 The Authors
- Inducible chromatin priming is associated with the establishment of immunological memory in T cells
- Sarah L Bevington1,
- Pierre Cauchy1,
- Jason Piper2,
- Elisabeth Bertrand3,
- Naveen Lalli2,
- Rebecca C Jarvis1,
- Liam Niall Gilding1,
- Sascha Ott2,
- Constanze Bonifer1 and
- Peter N Cockerill*,1
- 1Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK
- 2Warwick Systems Biology Centre, University of Warwick, Coventry, UK
- 3Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK
- ↵*Corresponding author. Tel: +44 121 4146841; E‐mail: p.n.cockerill{at}bham.ac.uk
Naïve T cells become epigenetically imprinted when activated and stably maintain regions of accessible active chromatin to support efficient reactivation of genes in primed T cells.
Synopsis
Naïve T cells become epigenetically imprinted when activated and subsequently they stably maintain regions of accessible active chromatin bound by ETS1 and RUNX1. These primed DNA elements support efficient reactivation of inducible genes in previously activated T cells.
Naïve T cells acquire a specific epigenetic imprint after initial T‐cell activation.
Primed T cells and memory‐phenotype cells retain a subset of accessible chromatin sites as DNase I‐hypersensitive sites.
ETS‐1 and RUNX1 remain bound to primed DNase I‐hypersensitive sites in previously activated T cells.
Primed DNase I‐hypersensitive sites facilitate inducible enhancer function.
The EMBO Journal (2016) 35: 515–535
- Received July 13, 2015.
- Revision received December 18, 2015.
- Accepted December 22, 2015.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Agile CD22 nanoclusters run rings around fenced BCR
B lymphocytes are key players in host defence, but also autoimmune diseases. Their survival depends upon tonic signals transduced by surface immunoglobulin (BCR) and the process leading to antibody secretion is initiated by interaction of BCR with a cognate antigen. CD22 limits signalling of the BCR to strike a balance between tonic signalling, reactivity to pathogens and prevention of autoimmunity. In this issue, Gasparrini et al (2016) combined super‐resolution imaging approaches with single‐particle tracking and simulations to show how CD22 controls the signalling state of the BCR. They demonstrated that small CD22 nanoclusters run rings around the BCR in confined steady state to maintain low tonic signals, but releasing BCR from these corrals allows BCR cluster growth, which overcomes the harrying inhibition from highly mobile CD22.
See also: F Gasparrini et al (February 2016)
Super‐resolution imaging approaches reveal how fast diffusion allows few molecules of CD22 to sample and inhibit a large number of immobile B‐cell receptor nanoclusters.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG‐I
- Su Jin Choi1,†,
- Hyun‐Cheol Lee2,†,
- Jae‐Hoon Kim2,
- Song Yi Park1,
- Tae‐Hwan Kim2,
- Woon‐Kyu Lee3,
- Duk‐Jae Jang2,
- Ji‐Eun Yoon4,
- Young‐Il Choi5,
- Seihwan Kim5,
- JinYeul Ma6,
- Chul‐Joong Kim2,
- Tso‐Pang Yao7,
- Jae U Jung8,
- Joo‐Yong Lee*,1 and
- Jong‐Soo Lee*,2
- 1Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, Korea
- 2College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon, Korea
- 3College of Medicine, Inha University, Incheon, Korea
- 4Foot and Mouth Disease Division, Animal Quarantine and Inspection Agency, Anyang, Korea
- 5CKD Research Institute, Yongin‐si Gyeonggi‐do, Korea
- 6Korean Medicine (KM) Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Korea
- 7Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
- 8Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- ↵*
Corresponding author. Tel: +82 42 821 8559; Fax: +82 42 821 8541; E‐mail: leejooyong{at}cnu.ac.kr
Corresponding author. Tel: +82 42 821 6753; Fax: +82 42 821 8903; E‐mail: jongsool{at}cnu.ac.kr
↵† These authors contributed equally to this work
Deacetylation of the cytoplasmic RIG‐I viral sensor by HDAC6 is required for viral RNA detection. HDAC6 depletion impairs in vivo responses against RNA but not DNA viruses in mice.
Synopsis
Deacetylation of the cytoplasmic RIG‐I viral sensor by HDAC6 is required for viral RNA detection. HDAC6 depletion impairs in vivo responses against RNA but not DNA viruses in mice.
HDAC6 interacts with and deacetylates RIG‐I in response to RNA virus infection.
Deacetylation of the K909 residue on RIG‐I regulates its viral RNA‐sensing activity.
HDAC6−/− mice are highly susceptible to RNA virus infection.
The EMBO Journal (2016) 35: 429–442
- Received July 17, 2015.
- Revision received November 16, 2015.
- Accepted December 8, 2015.
- © 2016 The Authors
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