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Article
| Open Access
Ancestral allele of DNA polymerase gamma modifies antiviral tolerance
The POLG1 mutation p.W748S, which is associated with mitochondrial recessive ataxia syndrome, dampens innate immune responses by compromising mtDNA replisome stability, and this explains why a viral infection can trigger the development of the disease and contribute to its variable clinical manifestation.
- Yilin Kang
- , Jussi Hepojoki
- & Anu Suomalainen
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Article
| Open Access
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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Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release
Macrophages are revealed to adopt a polymerase II pause/release process to effectively deal with ingested apoptotic corpses and for continuous efferocytosis.
- Turan Tufan
- , Gamze Comertpay
- & Kodi S. Ravichandran
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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
The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation
The ubiquitin proteasomal system degrades nuclear cGAS in cycling cells.
- Pengbiao Xu
- , Ying Liu
- & Andrea Ablasser
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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 insights into cytokine cleavage by inflammatory caspase-4
The human lipopolysaccharide receptor caspase-4 captures its cytokine substrate pro-IL-18 via a mechanism that is distinct from known caspase–substrate interactions, leading to inflammasome-independent IL-18 release from macrophages.
- Pascal Devant
- , Ying Dong
- & Jonathan C. Kagan
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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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Article
| Open Access
cGAS–STING drives ageing-related inflammation and neurodegeneration
The cGAS–STING signalling pathway is a critical driver of chronic inflammation and functional decline during ageing, and could be targeted to halt neurodegenerative processes during old age.
- Muhammet F. Gulen
- , Natasha Samson
- & Andrea Ablasser
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Structural mechanisms for regulation of GSDMB pore-forming activity
The cryo-EM structure of the GSDMB pore reveals mechanisms by which GSDMB pore-forming activity is regulated by pathogenic bacteria and mRNA splicing.
- Xiu Zhong
- , Huan Zeng
- & Jingjin Ding
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| Open Access
Structural basis for GSDMB pore formation and its targeting by IpaH7.8
The authors report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore, shedding light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and GSDMB pore formation.
- Chengliang Wang
- , Sonia Shivcharan
- & Jianbin Ruan
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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
| Open Access
Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence
Cap2 of the cyclic dinucleotide-based anti-phage immune system functions through a ubiquitin-like conjugation mechanism to regulate cGAS activity.
- Justin M. Jenson
- , Tuo Li
- & Zhijian J. Chen
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An E1–E2 fusion protein primes antiviral immune signalling in bacteria
This study demonstrates that bacteria use a ubiquitin transferase-like enzyme to prime cGAS/DncV-like nucleotidyltransferase activation and use a deubiquitinase-like enzyme to decrease activity.
- Hannah E. Ledvina
- , Qiaozhen Ye
- & Aaron T. Whiteley
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Article
| Open Access
Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
Dysfunctional telomeres activate innate immune responses through mitochondrial TERRA–ZBP1 complexes to eliminate cells that are destined for neoplastic transformation.
- Joe Nassour
- , Lucia Gutierrez Aguiar
- & Jan Karlseder
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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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R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response
RNA–DNA hybrids are immunogenic species that can aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response.
- Magdalena P. Crossley
- , Chenlin Song
- & Karlene A. Cimprich
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Recognition of cyclic dinucleotides and folates by human SLC19A1
Two cyclic dinucleotide molecules bind within the cavity of human SLC19A1 as a compact dual-molecule unit, whereas folate and antifolate bind to SLC19A1 as a monomer and occupy a distinct pocket of the cavity.
- Qixiang Zhang
- , Xuyuan Zhang
- & Pu Gao
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Article
| Open Access
Clathrin-associated AP-1 controls termination of STING signalling
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
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Article
| Open Access
A wheat resistosome defines common principles of immune receptor channels
Evolutionary conservation of plant receptor structure allowed for generation of new variants of wheat and barley nucleotide-binding leucine-rich repeat receptors (NLRs) that recognize AvrSr35 of the wheat stem rust pathogen, supporting proof of principle for structure-based engineering of NLRs for crop improvement.
- Alexander Förderer
- , Ertong Li
- & Jijie Chai
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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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A monocyte–leptin–angiogenesis pathway critical for repair post-infection
Monocytes recruited to skin infection are not involved in bacterial clearance but instead regulate local angiogenesis and healing.
- Rachel M. Kratofil
- , Hanjoo B. Shim
- & Paul Kubes
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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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| 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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| Open Access
Cryo-EM structure of an active bacterial TIR–STING filament complex
Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.
- Benjamin R. Morehouse
- , Matthew C. J. Yip
- & Philip J. Kranzusch
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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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Ablation of cDC2 development by triple mutations within the Zeb2 enhancer
The transcription factor NFIL3 acts antagonistically to C/EBP proteins by binding the Zeb2 enhancer to prevent Zeb2 expression and the development of the conventional type 2 dendritic cell lineage.
- Tian-Tian Liu
- , Sunkyung Kim
- & Kenneth M. Murphy
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Activation of STING by targeting a pocket in the transmembrane domain
The cryo-electron microscopy structure of human STING bound to both cyclic GMP-AMP and the small-molecule agonist C53 reveals an agonist-binding site in the STING transmembrane domain, and provides insight into the oligomerization and activation of STING.
- Defen Lu
- , Guijun Shang
- & Xuewu Zhang
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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
| Open Access
The cGAS–STING pathway drives type I IFN immunopathology in COVID-19
The cGAS–STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 infection.
- Jeremy Di Domizio
- , Muhammet F. Gulen
- & Andrea Ablasser
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Self-guarding of MORC3 enables virulence factor-triggered immunity
MORC3 is revealed as an essential negative regulator of the anti-viral interferon response that functions in an innate immune pathway that detects viral virulence factors.
- Moritz M. Gaidt
- , Alyssa Morrow
- & Russell E. Vance
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Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells
The improper timing of transforming growth factor-β production is a hallmark of severe COVID-19 that may impede natural killer cell function and early control of infection.
- Mario Witkowski
- , Caroline Tizian
- & Andreas Diefenbach
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eccDNAs are apoptotic products with high innate immunostimulatory activity
By developing a new eccDNA purification and profiling method, the study revealed close-to-random genomic origination, mechanism of biogenesis and function of eccDNAs.
- Yuangao Wang
- , Meng Wang
- & Yi Zhang
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AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence
AIM2 responds to infection with herpes simplex virus 1 or Francisella novicida by driving assembly of a large multi-protein complex containing multiple inflammasome sensors and cell death regulators.
- SangJoon Lee
- , Rajendra Karki
- & Thirumala-Devi Kanneganti
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Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C
The lysosomal protein Niemann–Pick type C1 (NPC1) is identified as a cofactor in the trafficking of STING, and loss of NPC1 is shown to both ‘prime’ and ‘boost’ STING signalling leading to neurological disease.
- Ting-Ting Chu
- , Xintao Tu
- & Nan Yan
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Article
| Open Access
cGAS-like receptors sense RNA and control 3′2′-cGAMP signalling in Drosophila
The authors identify Drosophila cGLR1 as a double-stranded RNA sensor and 3′2′-cGAMP as a nucleotide second messenger and activator of Drosophila STING signalling.
- Kailey M. Slavik
- , Benjamin R. Morehouse
- & Philip J. Kranzusch
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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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Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection
Upon Salmonella invasion of the mammalian cytosol, ubiquitylation of a non-proteinaceous substrate—the lipid A moiety of bacterial lipopolysaccharide—by the E3 ubiquitin ligase RNF213 marks the bacteria as cargo for antibacterial autophagy.
- Elsje G. Otten
- , Emma Werner
- & Felix Randow
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Gasdermin D pore structure reveals preferential release of mature interleukin-1
A cryo-electron microscopy study of the gasdermin D pore reveals a model of pore assembly and a charge-based mechanism for the preferential release of mature cytokines.
- Shiyu Xia
- , Zhibin Zhang
- & Hao Wu
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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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Skin-resident innate lymphoid cells converge on a pathogenic effector state
In studies using mouse models of psoriasis, a spectrum of innate lymphoid cell types is reconfigured and converges via multiple trajectories on a type 3-like state, demonstrating the range and flexibility of innate lymphoid cell responses in the skin.
- Piotr Bielecki
- , Samantha J. Riesenfeld
- & Richard A. Flavell
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Sorting nexin 5 mediates virus-induced autophagy and immunity
Genome-wide siRNA screens identify an essential function for sorting nexin 5 in virus-induced autophagy and immunity mediated via class III phosphatidylinositol-3-kinase complex 1.
- Xiaonan Dong
- , Yuting Yang
- & Beth Levine
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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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The molecular basis of tight nuclear tethering and inactivation of cGAS
Structural studies show that cyclic GMP–AMP synthase binds to nucleosomes through its DNA-binding site, which maintains it in an inactive conformation and prevents self-DNA binding.
- Baoyu Zhao
- , Pengbiao Xu
- & Pingwei Li
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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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STING cyclic dinucleotide sensing originated in bacteria
Structures of prokaryotic homologues of STING permit the reconstruction of the evolutionary trajectory of its incorporation into metazoan innate immunity, and reveal a role for the conserved cGAS–STING pathway in prokaryotic defence against bacteriophages.
- Benjamin R. Morehouse
- , Apurva A. Govande
- & Philip J. Kranzusch
