Signal transduction articles within Nature

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  • Article
    | Open Access

    Learning results in persistent double-stranded DNA breaks, nuclear rupture and release of DNA fragments and histones within hippocampal CA1 neurons that, following TLR9-mediated DNA damage repair, results in their recruitment to memory circuits.

    • Vladimir Jovasevic
    • , Elizabeth M. Wood
    •  & Jelena Radulovic

  • Article
    | Open Access

    The adaptor protein AP-1 controls the shutdown of STING signalling through a mechanism in which AP-1 recognizes a dileucine motif in phosphorylated STING, which leads to targeted transport of STING to the endolysosomal system for degradation.

    • Ying Liu
    • , Pengbiao Xu
    •  & Andrea Ablasser

  • Article
    | Open Access

    Cryo-electron microscopy structures of IL-25–IL-17RB–IL-17RA and IL-17A–IL-17RC–IL-17RA complexes show a tip-to-tip architecture, which is a key organizing principle of the IL-17 receptor family.

    • Steven C. Wilson
    • , Nathanael A. Caveney
    •  & K. Christopher Garcia

  • Article |

    CRISPR screening and protein–protein interaction networks identify components and mechanisms of nutrient-dependent mTORC1 signalling in regulatory T cells and reveal how mTORC1 integrates immunological cues and nutrient signals for adaptive immunity.

    • Lingyun Long
    • , Jun Wei
    •  & Hongbo Chi

  • Article |

    IFITM3 shifts upon phosphorylation from acting as an antiviral effector to being a scaffold for PIP3 and thereby amplifies PI3K signalling, which can be co-opted for malignant transformation in B cell leukaemia and lymphoma.

    • Jaewoong Lee
    • , Mark E. Robinson
    •  & Markus Müschen

  • Article |

    Using cryo-electron microscopy, the authors determine the structure of cGAS bound to nucleosomes and present evidence for the mechanism by which nucleosome binding to cGAS prevents cGAS dimerization and its binding to free double-stranded DNA.

    • Ganesh R. Pathare
    • , Alexiane Decout
    •  & Andrea Ablasser

  • Article |

    The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.

    • Leonhard X. Heinz
    • , JangEun Lee
    •  & Giulio Superti-Furga

  • Letter |

    A genome-wide CRISPR-interference screen is used to identify the reduced folate carrier SLC19A1 as the major transporter of cyclic dinucleotides in human cells, with potential roles in immunotherapeutic treatment of cancer, immune responses to pathogens and inflammatory diseases.

    • Rutger D. Luteijn
    • , Shivam A. Zaver
    •  & David H. Raulet

  • Letter |

    The discovery and characterization of small-molecule antagonists that inhibit the stimulator of interferon genes (STING) protein may help to develop therapies for the treatment of autoinflammatory disease.

    • Simone M. Haag
    • , Muhammet F. Gulen
    •  & Andrea Ablasser

  • Letter |

    A pro-survival multiprotein signalling supercomplex consisting of the B cell receptor, MYD88, TLR9 and mTOR is discovered that coordinates NF-κB activation in diffuse large B cell lymphoma, and provides mechanistic insight into the efficacy of drug combinations.

    • James D. Phelan
    • , Ryan M. Young
    •  & Louis M. Staudt

  • Letter |

    The cytoplasmic DNA receptor cGAS catalyses the synthesis of the second messenger cGAMP, which in turn activates type I interferon via STING; this study shows that cGAMP is transmitted to neighbouring cells via gap junction channels and activates STING, thus inducing an antiviral state in these bystander cells independent of paracrine interferon signalling.

    • Andrea Ablasser
    • , Jonathan L. Schmid-Burgk
    •  & Veit Hornung

  • Letter |

    A genome-wide RNA interference analysis identifies the septin family of cytoskeletal filaments as important regulators of store-operated Ca2+ entry into the cell; septins are shown to organize plasma membrane microdomains important in STIM1 and ORAI1 signalling, and may also be relevant in membrane microdomains underlying other signalling processes.

    • Sonia Sharma
    • , Ariel Quintana
    •  & Patrick G. Hogan

  • Letter |

    Interleukin-1β-induced disruption to endothelial stability and vascular permeability in a human in vitro model is shown to be independent of downstream nuclear factor-κB activation, relying instead on a MYD88–ARNO–ARF6 signalling cascade; inhibiting proteins involved in this pathway is shown to improve outcomes in animal models of inflammatory disease.

    • Weiquan Zhu
    • , Nyall R. London
    •  & Dean Y. Li

  • Letter |

    B-cell receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL) is found not to be dependent on exogenous antigens; instead, signalling may involve the binding of the BCR heavy-chain complementarity-determining region to self epitopes on the same receptor, a finding that may have important implications for understanding the pathogenesis of CLL and potential therapeutic approaches.

    • Marcus Dühren-von Minden
    • , Rudolf Übelhart
    •  & Hassan Jumaa

  • News & Views |

    Recognition of aberrant cell death is a crucial function of the immune system. It seems that one way in which immune cells identify damage is by sensing actin, an abundant intracellular protein.

    • Gordon D. Brown

  • News & Views |

    Magnesium binds to enzymes and nucleic acids and is essential for their activity. It emerges that this ion can also function as a signalling molecule with a crucial role in the immune system. See Article p.471

    • Ning Wu
    •  & André Veillette

  • Letter |

    The ubiquitin conjugation system regulates the canonical NF-κB-activation pathway, which mediates immune responses. Linear polyubiquitin chains—in which the C-terminal glycine of ubiquitin is conjugated to the α-amino group of the amino-terminal methionine of another ubiquitin—are generated by a unique ubiquitin ligase complex called linear ubiquitin chain assembly complex (LUBAC) composed of two RING domain proteins called HOIL-1 and HOIP. This is one of three complementary studies identifying a novel component of the LUBAC complex called SHARPIN, which is recruited to receptor signalling complexes (RSCs) that form after TNF and CD40L stimulation. The LUBAC complex containing SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo and is required for the activation of NF-κB signalling.

    • Fuminori Tokunaga
    • , Tomoko Nakagawa
    •  & Kazuhiro Iwai

  • Letter |

    The ubiquitin conjugation system regulates the canonical NF-κB activation pathway, which mediates immune responses. Linear polyubiquitin chains—in which the C terminal glycine of ubiquitin is conjugated to the α-amino group of the amino-terminal methionine of another ubiquitin—are generated by a unique ubiquitin ligase complex called linear ubiquitin chain assembly complex (LUBAC) composed of two RING domain proteins called HOIL-1 and HOIP. This is one of three complementary studies identifying a novel component of the LUBAC complex called SHARPIN, which is recruited to receptor signalling complexes (RSCs) that form after TNF and CD40L stimulation. The LUBAC complex containing SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo and is required for the activation of NF-κB signalling.

    • Fumiyo Ikeda
    • , Yonathan Lissanu Deribe
    •  & Ivan Dikic

  • Letter |

    A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here, 33 distinct enhancers within this region are identified, showing that SNPs in one of the enhancers affect STAT1 binding. Furthermore, it is shown that in human vascular endothelial cells the enhancer interval physically interacts with a number of specific loci and that IFN-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes.

    • Olivier Harismendy
    • , Dimple Notani
    •  & Kelly A. Frazer

  • Letter |

    This study finds frequent mutations in MYD88 in the activated B-cell-like subtype of diffuse large B-cell lymphoma and, with lower frequency, in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, are shown to activate the pathway and promote cancer cell survival.

    • Vu N. Ngo
    • , Ryan M. Young
    •  & Louis M. Staudt

  • Letter |

    Apoptotic cells discharge ATP and UTP, which act as 'find-me' signals for phagocytes that in turn engulf dying cells before potentially harmful cellular contents are released. These authors show that the release of ATP and UTP is exclusively by means of the plasma membrane channel pannexin 1, which is opened specifically by caspase activity.

    • Faraaz B. Chekeni
    • , Michael R. Elliott
    •  & Kodi S. Ravichandran

  • Letter |

    The pre-T-cell antigen receptor mediates early T-cell development and differentiation. These authors report its structure and explain how the head-to-tail dimeric arrangement allows the interaction of the pre-Tα domain with any variable β domain, and provides the basis for ligand-independent signalling.

    • Siew Siew Pang
    • , Richard Berry
    •  & Jamie Rossjohn

  • Letter |

    Multicellular organisms, particularly their immune systems, rely on complex cell-to-cell communication, mediated by signalling molecules that form spatiotemporal concentration gradients. Here, high-throughput microfluidic cell culture and fluorescence microscopy, together with quantitative gene expression analysis and mathematical modelling, have been used to investigate how mammalian cells respond to different levels of TNF-α and signal to NF-κB. Both digital and analogue responses are revealed.

    • Savaş Tay
    • , Jacob J. Hughey
    •  & Markus W. Covert

  • Letter |

    Engagement of the tumour-necrosis factor (TNF) receptor results in the assembly of multi-component signalling complexes by adaptor proteins that include TNF receptor-associated factor 2 (TRAF2). Genetic evidence indicates that TRAF2 is needed for the polyubiquitination of receptor interacting protein 1 (RIP1), but direct evidence has been lacking. Here it is shown that the lipid sphingosine-1-phosphate is a co-factor needed for this ubiquitination activity of TRAF2.

    • Sergio E. Alvarez
    • , Kuzhuvelil B. Harikumar
    •  & Sarah Spiegel

  • News & Views |

    Toll receptors trigger immune responses through adaptor proteins and kinase enzymes. Structural studies reveal that hierarchical assembly of these proteins into a helical tower initiates downstream signalling events.

    • Steven A. Wasserman

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