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Formation of memory assemblies through the DNA-sensing TLR9 pathway
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
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Structures and activation mechanism of the Gabija anti-phage system
Structures of complexes containing GajA and GajB proteins of the prokaryotic Gabija anti-phage defence system reveal the mechanism of its activation after DNA cleavage upon ATP depletion.
- Jing Li
- , Rui Cheng
- & Longfei Wang
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Article
| Open Access
IL-10 constrains sphingolipid metabolism to limit inflammation
IL-10 exerts its anti-inflammatory activity in macrophages by increasing the expression of enzymes that promote fatty acid desaturation and downstream regulation of the transcription factor REL.
- Autumn G. York
- , Mathias H. Skadow
- & Richard A. Flavell
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Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome
Structural and mutational studies and cellular assays show that the inflammasome sensor NLRP1 forms a complex with thioredoxin, which acts as a negative regulator of inflammasome activity.
- Zhikuan Zhang
- , Takuma Shibata
- & Toshiyuki Shimizu
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Macrophage fumarate hydratase restrains mtRNA-mediated interferon production
Inhibition of the tricarboxylic acid cycle enzyme fumarate hydratase leads to deregulation of cytokine production in macrophages, which has implications in human diseases such as systemic lupus erythematosus.
- Alexander Hooftman
- , Christian G. Peace
- & Luke A. J. O’Neill
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Article |
mRNA ageing shapes the Cap2 methylome in mammalian mRNA
Cap2 methylation increases on transcripts as they age, reducing activation of innate immunity.
- Vladimir Despic
- & Samie R. Jaffrey
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Article
| Open Access
Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation
N-acetylglucosamine kinase catalyses the phosphorylation of muramyl dipeptide and is thus essential for its recognition and immunostimulatory activity in human and mouse cells.
- Che A. Stafford
- , Alicia-Marie Gassauer
- & Veit Hornung
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Article |
RNA editing underlies genetic risk of common inflammatory diseases
cis-RNA editing quantitative trait loci, which are associated with immunogenic double-stranded RNAs, underlie genome-wide association study variants in common autoimmune and inflammatory diseases.
- Qin Li
- , Michael J. Gloudemans
- & Jin Billy Li
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Article
| Open Access
ADAR1 averts fatal type I interferon induction by ZBP1
ADAR1 prevents Z-RNA-dependent activation of pathogenic type I interferon responses by ZBP1, whose activity may contribute to pathology in type I interferonopathies with ADAR1 mutations.
- Huipeng Jiao
- , Laurens Wachsmuth
- & Manolis Pasparakis
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ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation
In addition to its role in suppressing MDA5 and PKR activation, ADAR1 is a negative regulator of ZPB1-mediated apoptosis and necroptosis, providing insights into the pathology of Aicardi–Goutières syndrome.
- Richard de Reuver
- , Simon Verdonck
- & Jonathan Maelfait
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Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis
The Streptococcus pyogenes virulence factor SpeB triggers pyroptosis in keratinocytes by catalysing cleavage of host gasdermin A, a key event triggering the immune response to S. pyogenes infection.
- Wanyan Deng
- , Yang Bai
- & Xing Liu
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Article |
Two cGAS-like receptors induce antiviral immunity in Drosophila
Two cGAS-like receptors, cGLR1 and cGLR2, identified in Drosophila melanogaster are shown to induce antiviral immunity in response to RNA or DNA virus infections through the production of 2′3′-cGAMP and 3′2′-cGAMP.
- Andreas Holleufer
- , Kasper Grønbjerg Winther
- & Rune Hartmann
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DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation
Structures of NLRP1–DPP9 alone and with a small-molecule inhibitor of DPP9 reveal the mechanisms through which NLRP1 is regulated, providing insights into the role of this complex in inflammasome regulation.
- L. Robert Hollingsworth
- , Humayun Sharif
- & Hao Wu
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Article
| Open Access
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9
The 2:1 complex between the inflammatory mediator NLRP1 and the dipeptidyl peptidase DPP9 functions to sequester an inflammasome-forming fragment of NLRP1 and enhance NLRP1 autoinhibition.
- Menghang Huang
- , Xiaoxiao Zhang
- & Jijie Chai
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Galactosaminogalactan activates the inflammasome to provide host protection
Galactosaminogalactan of Aspergillus fumigatus acts as a pathogen-associated molecular pattern that activates the NLRP3 inflammasome, which is crucial for anti-fungal host defence.
- Benoit Briard
- , Thierry Fontaine
- & Thirumala-Devi Kanneganti
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Integration of innate immune signalling by caspase-8 cleavage of N4BP1
NEDD4-binding protein 1 (N4BP1) is identified as a suppressor of cytokine production that is inactivated by caspase-8, which provides insight into the mechanisms underlying the immunodeficiency caused by mutations in FADD and caspase-8.
- Alexander D. Gitlin
- , Klaus Heger
- & Vishva M. Dixit
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Structural mechanism of cGAS inhibition by the nucleosome
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
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Structural basis for sequestration and autoinhibition of cGAS by chromatin
Biochemical and structural analyses show how tethering of the nucleotidyltransferase cGAS to chromatin prevents autoimmune recognition of nuclear DNA.
- Sebastian Michalski
- , Carina C. de Oliveira Mann
- & Karl-Peter Hopfner
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TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9
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
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UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity
The interaction of UNC93B1 with syntenin-1 facilitates the sorting of TLR7–UNC93B1 complexes into intraluminal vesicles of multivesicular bodies, and mutations in UNC93B1 that disrupt such interactions lead to enhanced TLR7 signalling and autoimmunity.
- Olivia Majer
- , Bo Liu
- & Gregory M. Barton
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Release from UNC93B1 reinforces the compartmentalized activation of select TLRs
The Toll-like receptor TLR9 is activated only after regulated release from its trafficking chaperone UNC93B1, which occurs within endosomes and is required for ligand binding and signal transduction.
- Olivia Majer
- , Bo Liu
- & Gregory M. Barton
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Letter |
DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome
The RNA helicase DDX3X has a critical role in regulating both the induction of stress granules and the activation of the NLRP3 inflammasome in cells under stress conditions.
- Parimal Samir
- , Sannula Kesavardhana
- & Thirumala-Devi Kanneganti
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Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome
A cryo-electron microscopy structure of human NLRP3 in complex with the mitotic kinase NEK7 provides insights into the interactions that mediate the activation of the NLRP3 inflammasome.
- Humayun Sharif
- , Li Wang
- & Hao Wu
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Letter |
Structural basis of STING binding with and phosphorylation by TBK1
The cryo-electron microscopy structure of human TBK1 in complex with cyclic GMP–AMP-bound chicken STING reveals a binding mode that suggests that STING phosphorylation by TBK1 requires oligomerization of both proteins.
- Conggang Zhang
- , Guijun Shang
- & Zhijian J. Chen
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Letter |
Autophagy induction via STING trafficking is a primordial function of the cGAS pathway
The authors report that the cGAS–STING pathway drives a form of autophagy that is independent of interferon induction and distinct from the conventional autophagy.
- Xiang Gui
- , Hui Yang
- & Zhijian J. Chen
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Letter |
Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP
Cryo-electron microscopy structures of full-length STING show that cyclic GMP–AMP induces a half-turn rotation of the ligand-binding domain relative to the transmembrane domain, forming a tetramer and higher-order oligomers for signalling.
- Guijun Shang
- , Conggang Zhang
- & Xuewu Zhang
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Bacterial cGAS-like enzymes synthesize diverse nucleotide signals
A bacterial family of cGAS/DncV-like nucleotidyltransferases synthesizes a diverse range of cyclic dinucleotide and trinucleotide compounds that are likely to modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts.
- Aaron T. Whiteley
- , James B. Eaglesham
- & Philip J. Kranzusch
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Letter |
Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose
The bacterial metabolite ADP-heptose activates NF-κB in host cells via alpha-kinase 1 and the TIFA–TRAF signalling pathway.
- Ping Zhou
- , Yang She
- & Feng Shao
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Letter |
Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition
Age-dependent epithelial expression of the innate immune receptor TLR5 in the gut of newborn mice selects against the presence of flagellated bacteria and influences microbiota composition throughout life.
- Marcus Fulde
- , Felix Sommer
- & Mathias W. Hornef
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Article |
New mitochondrial DNA synthesis enables NLRP3 inflammasome activation
New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.
- Zhenyu Zhong
- , Shuang Liang
- & Michael Karin
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Letter |
Mitochondrial double-stranded RNA triggers antiviral signalling in humans
Mitochondrial double-stranded RNA can induce an interferon response if released into the cytoplasm, but self-recognition is prevented by SUV3 helicase and PNPase exoribonuclease.
- Ashish Dhir
- , Somdutta Dhir
- & Nicholas J. Proudfoot
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Letter |
Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis
The immunoregulatory metabolite itaconate and its dimethyl derivative induce electrophilic stress and react with glutathione to induce both Nrf2-dependent and Nrf2-independent responses, resulting in AF3-mediated inhibition of the inflammation-related protein IκBζ.
- Monika Bambouskova
- , Laurent Gorvel
- & Maxim N. Artyomov
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Letter |
Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus
The C-type lectin receptor MelLec recognizes DHN-melanin in conidial spores of Aspergillus fumigatus and other DHN-melanized fungi, revealing an important role for this receptor in antifungal immunity in both mice and humans.
- Mark H. T. Stappers
- , Alexandra E. Clark
- & Gordon D. Brown
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Letter |
CG dinucleotide suppression enables antiviral defence targeting non-self RNA
Vertebrate genomes contain fewer CG dinucleotides than would be expected by chance, and this pattern is mimicked by many viruses; HIV-1 derivatives mutated to contain more CG dinucleotides are targeted by the human antiviral protein ZAP, suggesting that CG suppression has evolved in viruses to evade recognition.
- Matthew A. Takata
- , Daniel Gonçalves-Carneiro
- & Paul D. Bieniasz
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Letter |
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein–DNA ladders
A molecular mechanism for the sensitive detection of long and U-turn DNA by cyclic GMP–AMP synthase (cGAS) both in vitro and in human cells.
- Liudmila Andreeva
- , Björn Hiller
- & Karl-Peter Hopfner
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Letter |
cGAS surveillance of micronuclei links genome instability to innate immunity
The cytoplasmic DNA sensor cGAS detects DNA in ruptured micronuclei and activates an innate immune response.
- Karen J. Mackenzie
- , Paula Carroll
- & Andrew P. Jackson
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Letter |
Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells
The inflammasome receptor Nlrp9b defends against enteric viruses by interacting with double-stranded viral RNA-bound helicase Dhx9, triggering gasdermin-D-dependent pyroptotic cell death of infected cells and secretion of Il-18.
- Shu Zhu
- , Siyuan Ding
- & Richard A. Flavell
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Letter |
Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets
Human TRIM5α restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway.
- Carla M. S. Ribeiro
- , Ramin Sarrami-Forooshani
- & Teunis B. H. Geijtenbeek
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Brief Communications Arising |
Does caspase-12 suppress inflammasome activation?
- Lieselotte Vande Walle
- , Daniel Jiménez Fernández
- & Mohamed Lamkanfi
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Letter |
NOD1 and NOD2 signalling links ER stress with inflammation
A novel link between the unfolded protein response and NOD1/2 innate immune signalling, showing that NOD1/2 are required for ER-stress-induced IL-6 production in response to infection with Brucella abortus.
- A. Marijke Keestra-Gounder
- , Mariana X. Byndloss
- & Renée M. Tsolis
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Letter |
NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux
NEK7, a member of the NIMA-related kinase family, is identified as a regulator of NLRP3 inflammasome oligomerization and activation; NEK7 functions downstream of potassium efflux in a manner that is independent of its kinase activity.
- Yuan He
- , Melody Y. Zeng
- & Gabriel Núñez
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Article |
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Gasdermin D is identified as the required substrate for pyroptosis, mediating caspase-11 function in the non-canonical inflammasome pathway; the cleaved N-terminal domain is shown to trigger pyroptosis.
- Nobuhiko Kayagaki
- , Irma B. Stowe
- & Vishva M. Dixit
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Letter |
Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9
Crystal structures of three forms of Toll-like receptor (TLR) 9 — unliganded or bound either to immune stimulatory CpG-containing DNA or inhibitory DNA — together reveal the molecular basis of TLR9 activation.
- Umeharu Ohto
- , Takuma Shibata
- & Toshiyuki Shimizu
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Article |
AhR sensing of bacterial pigments regulates antibacterial defence
The mammalian aryl hydrocarbon receptor (known to sense environmental pollutants) is shown to also have a role as a pattern recognition receptor in sensing bacterial virulence factors, resulting in an antibacterial response and activation of innate and natural defences.
- Pedro Moura-Alves
- , Kellen Faé
- & Stefan H. E. Kaufmann
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Letter |
Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates
The innate immune receptor RIG-I is shown to sense 5′-diphosphate RNAs as found in some viral genomes in addition to its well characterized activation by RNAs bearing 5′-triphosphate moieties.
- Delphine Goubau
- , Martin Schlee
- & Caetano Reis e Sousa
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Article |
Aryl hydrocarbon receptor control of a disease tolerance defence pathway
Initial exposure to lipopolysaccharide (LPS) induces endotoxin tolerance, which reduces immunological reactions to LPS; here it is shown that primary LPS challenge is controlled by AhR, TDO2 and IL-10, whereas sustained effects require AhR, IDO1 and TGF-β, allowing for disease tolerance with reduced immunopathology in infections.
- Alban Bessede
- , Marco Gargaro
- & Paolo Puccetti
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Letter |
Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis
Pathogenesis of rheumatoid arthritis depends critically on the NLRP3 inflammasome/interleukin-1 signalling axis.
- Lieselotte Vande Walle
- , Nina Van Opdenbosch
- & Mohamed Lamkanfi
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Letter |
Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome
The Pyrin inflammasome detects the presence of a pathogen not through recognition of a microbial molecule but by the activity of a bacterial toxin that modifies host Rho activity.
- Hao Xu
- , Jieling Yang
- & Feng Shao
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Letter |
Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases
Interferon-inducible GTPases are required for the release of vacuolar Gram-negative bacteria into the cytoplasm and subsequent inflammasome-mediated caspase-11 activation.
- Etienne Meunier
- , Mathias S. Dick
- & Petr Broz
Ancestral allele of DNA polymerase gamma modifies antiviral tolerance