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| Open AccessToll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen
Fungal pathogens are recognised and phagocytosed by macrophages in the early stages of infection. Here, Onyishi et al. identify a crosstalk between Toll Like Receptor 4 and Macrophage Scavenger Receptor 1 in the regulation of Cryptococcus neoformans uptake.
- Chinaemerem U. Onyishi
- , Guillaume E. Desanti
- & Robin C. May
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Article
| Open AccessWDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response
MAVS aggregation initiates innate immune defences and is closely regulated to limit excessive inflammation. Here, Li et al identify and characterise a negative regulator of MAVS signalling and its impact on virus infection.
- Jiaxin Li
- , Rui Zhang
- & Fajian Hou
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Article
| Open AccessHigh-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation
HLA-E is a highly conserved MHC-l recognized by NK and T cells. The authors characterize HLA-E-presented peptides recognized by CD94/NKG2x, identifying human and CMV-derived peptide ligands which can modulate NK cell activity when presented by HLA-E, including for selective NK cell activation.
- Brooke D. Huisman
- , Ning Guan
- & Michael E. Birnbaum
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Article
| Open AccessCryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer
ISGylation plays a crucial role in the innate immune response and requires sequential activity of E1, E2, and E3 enzymes. Here, the authors present cyro-EM structures that reveal the molecular mechanisms underlying ISG15 activation by the E1 enzyme Uba7 and transfer to its cognate E2 enzyme UBE2L6.
- Mohammad Afsar
- , GuanQun Liu
- & Shaun K. Olsen
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| Open AccessIL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation
The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.
- Vishwas Mishra
- , Anna Crespo-Puig
- & Avinash R. Shenoy
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Article
| Open AccessHigh body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection
The ambient environmental temperature changes the extent or severity of a virus infection. Here the authors show that influenza and SARS-CoV-2 infection at higher temperatures promotes gut microbiota derived deoxycholic acid signalling which increases host resistance to infection.
- Minami Nagai
- , Miyu Moriyama
- & Takeshi Ichinohe
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Article
| Open AccessSingle cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome
Paediatric acute respiratory distress syndrome (pARDS) is associated with significant mortality and morbidity. Here the authors use single cell sequencing of tracheal aspirate samples from children with pARDS and characterise immune phenotypes and associations with infection stage and pathogen.
- Tim Flerlage
- , Jeremy Chase Crawford
- & Paul G. Thomas
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Article
| Open AccessThe mRNA methyltransferase Mettl3 modulates cytokine mRNA stability and limits functional responses in mast cells
The m6A mRNA modification is essential for immune cell function. Here, the Monticelli lab optimized methods of gene editing by CRISPR-Cas9 in mast cells and revealed how the m6A machinery is required to sustain proliferation and to limit the production of inflammatory cytokines by these cells.
- Cristina Leoni
- , Marian Bataclan
- & Silvia Monticelli
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Article
| Open AccessSelective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis
Ulcerative colitis is associated with increased infiltration and cellularity, yet the precise tissue topology remains poorly understood. Here the authors employ imaging mass cytometry and single-cell RNA sequencing to characterise intestinal lesions in patients with ulcerative colitis, and show the architecture at the individual cell level which includes a decrease in the resident macrophage population.
- Juan Du
- , Junlei Zhang
- & Jianpeng Sheng
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Article
| Open AccessSingle cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis
Changes in Psoriasis and other inflammatory skin diseases during severity stages can be investigated using single cell and spatial transcriptomics. Here the authors compare different inflammatory skin diseases to emphasise differences in immune cells and inflammatory markers particularly keratinocytes and fibroblasts.
- Feiyang Ma
- , Olesya Plazyo
- & Johann E. Gudjonsson
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Article
| Open AccessSingle cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils
Single cell sequencing can be used to better characterize immune cell progenitors. Here the authors characterize CLEC12Ahi pre-basophils downstream of pre-basophil and mast cell progenitors (pre-BMPs) but upstream of mature basophils and this population includes basophil progenitors (BaPs).
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessPRMT1 mediated methylation of cGAS suppresses anti-tumor immunity
cGAS/STING mediated immunity is linked to the anti-tumor response, but how tumor-intrinsic cGAS signals are countered during tumorigenesis and immune evasion is poorly understood. Here the authors show PRMT1 suppresses the anti-tumor immune response via arginine methylation of cGAS.
- Jing Liu
- , Xia Bu
- & Wenyi Wei
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Article
| Open AccessPrenylcysteine oxidase 1 like protein is required for neutrophil bactericidal activities
Neutrophils play critical roles in the response to infection and their function relies on a range of intrinsic and extrinsic factors. Here the authors show a role for Pcyox1l and link this to metabolic pathways including prenylation and the neutrophil response to infection.
- Anastasiia Petenkova
- , Shelby A. Auger
- & Mihaela Gadjeva
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Article
| Open AccessRhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19
Viral infections and exposure to inhaled allergens are linked to asthma onset, exacerbations and progression. Here, the authors used controlled experimental rhinovirus infection in patients with and without asthma, and further assessed in vitro the role of house dust mite allergen combined with rhinovirus and SARS-CoV-2 infection. They discovered that rhinovirus-induced activation of epithelial RIG-I inflammasome supresses antiviral immunity, promotes inflammation during asthma exacerbations and aggravates subsequent infection with SARS-CoV-2, particularly upon house dust mite exposure.
- Urszula Radzikowska
- , Andrzej Eljaszewicz
- & Milena Sokolowska
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Article
| Open AccessA bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3
Innate immune evasion is a key aspect of bacterial pathogenesis. Here, Ta et al identify and characterise EhaF, a bacterial autotransporter that functions to inhibit host innate immunity and promote the colonisation and pathogenesis of enterohemorrhagic Escherichia coli.
- Atri Ta
- , Rafael Ricci-Azevedo
- & Sivapriya Kailasan Vanaja
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Article
| Open AccessSerum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model
The immune response has been suggested to be involved in the pathology of Ménière’s disease. Here the authors implicate serum glucocorticoid-inducible kinase 1 as a regulator of the NLRP3 inflammasome and link to macrophage function in a model of Ménière’s disease pathology.
- Dao-Gong Zhang
- , Wen-Qian Yu
- & Hai-Bo Wang
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Article
| Open AccessCrocodile defensin (CpoBD13) antifungal activity via pH-dependent phospholipid targeting and membrane disruption
Defensins are a class of host defence peptides that contribute to the immune system of eukaryotes. Here, the authors report the structure of saltwater crocodile defensin CpoBD13 and the mechanism of pH-dependent antifungal activity.
- Scott A. Williams
- , Fung T. Lay
- & Mark D. Hulett
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Article
| Open AccessGasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection
Here, de Sá et al. show that Gasdermin-D is transiently activated in Leishmania-infected macrophages and promotes NLRP3 inflammasome activation, but not cell death. Gasdermin-D is cleaved into a noncanonical fragment, indicating that Leishmania subverts Gasdermin-D-mediated host response to establish leishmaniasis.
- Keyla S. G. de Sá
- , Luana A. Amaral
- & Dario S. Zamboni
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Article
| Open AccessAPOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection
APOBEC’s are a family of cytidine deaminases that induce mutations in viruses to inhibit their replication and maintain cell integrity. Here, Manjunath et al show that APOBEC3B also inhibits viral replication by stimulating the innate immune sensor protein kinase R causing translational shutdown and stress granule formation independently of its cytidine deaminase activity.
- Lavanya Manjunath
- , Sunwoo Oh
- & Rémi Buisson
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Article
| Open AccessMyristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation
Stimulator of interferon gene (STING) plays critical roles in the host response to infection and in the production of interferon. Here the authors suggests myristic acid is involved in the homeostatic balancing of STING dependent autophagy and the interferon response.
- Mutian Jia
- , Yuanyuan Wang
- & Wei Zhao
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Article
| Open AccessMicrobiota-derived acetate enhances host antiviral response via NLRP3
The NLRP3 inflammasome plays a pivotal role in clearing viral respiratory infection, but the molecular mechanism is not fully known. Here authors show that acetate, produced by gut bacteria, may enhance NLRP3-mediated type I interferon production following influenza infection in mice.
- Junling Niu
- , Mengmeng Cui
- & Guangxun Meng
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Article
| Open AccessESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling
STING is an intracellular sensor of pathogen- or host-derived DNA. In this study, the authors identify an ESCRT complex that regulates STING degradation, thus acting as a homeostatic regulator of STING signalling and type-I interferon responses.
- Matteo Gentili
- , Bingxu Liu
- & Nir Hacohen
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Article
| Open AccessIncreased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development
The contribution of transposable elements and endogenous retroviruses to renal fibroinflammation is currently unknown. Here, the authors comprehensively profile the expression of transposable elements and endogenous retroviruses (ERVs) in kidneys of patients and mouse disease models and find expression of ERVs in diseased kidneys activate cytosolic nucleotide sensors contributing to cytokine release and renal fibroinflammation.
- Poonam Dhillon
- , Kelly Ann Mulholland
- & Katalin Susztak
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| Open AccessThe interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
Proteomic analyses revealed that a group of interferon-stimulated genes suppresses LINE-1 retrotransposon activities, including HELZ2, which reduces LINE-1 RNA and the associated innate immune response levels.
- Ahmad Luqman-Fatah
- , Yuzo Watanabe
- & Tomoichiro Miyoshi
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Article
| Open AccessTLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction
TLR3 activates a potent immune response by binding to dsRNA. Here the authors report cryo-EM analyses to show that TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.
- Kentaro Sakaniwa
- , Akiko Fujimura
- & Toshiyuki Shimizu
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Article
| Open AccessAntiretroviral APOBEC3 cytidine deaminases alter HIV-1 provirus integration site profiles
Antiretroviral APOBEC3 may contribute to HIV-1 latency. In this study, Ajoge and Renner et al. identify a previously undescribed function of human APOBEC3 proteins in redirecting integrations of HIV-1 DNA into more transcriptionally inactive regions of the genome.
- Hannah O. Ajoge
- , Tyler M. Renner
- & Stephen D. Barr
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| Open AccessDefective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity
The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.
- Nikaïa Smith
- , Céline Possémé
- & Darragh Duffy
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Article
| Open AccessAlveolar macrophage metabolic programming via a C-type lectin receptor protects against lipo-toxicity and cell death
Alveolar macrophages (AM) in the lungs maintain surfactant during homeostasis and respond to infectious pathogens. Here the authors show that in the absence of NKR-P1B, pneumococcal infection is more severe because KO AM have increased rates of lipid surfactant uptake and reduced anti-microbial function.
- Michal Scur
- , Ahmad Bakur Mahmoud
- & Andrew P. Makrigiannis
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| Open AccessStructural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation
TRIM5α is an E3 ligase that inhibits retroviral replication. Here, the authors delineate the biochemical mechanism that accelerates N terminal autoubiquitylation of TRIM5α upon its association with the retroviral capsid and, thus, enables recognition of an infection-associated molecular pattern.
- Frank Herkules
- , Corey H. Yu
- & Dmitri N. Ivanov
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Article
| Open AccessDNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance
DNA is well-documented to stimulate immune response. Here the authors show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, itself determined by DNA-sequence, damage and length.
- Lina Wang
- , Siru Li
- & Qingkai Yang
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Article
| Open AccessRasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth
IL-6 and RasGRP1 have been shown to have important functions during inflammation and cancer. Here the authors propose the protein and mRNA of RasGRP1 have opposing functions by promoting IL-6 mediated acute inflammation and inhibiting inflammation-associated cancer through mRNA and protein mechanisms respectively.
- Cong Wang
- , Xue Li
- & Songqing Tang
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Article
| Open AccessInterruption of post-Golgi STING trafficking activates tonic interferon signaling
Microbial DNA is recognized by the cGAS-STING pathway, which leads to a type I interferon response. Here authors show that a basal flux of interferon activation could also be triggered by interference with STING trafficking from the Golgi apparatus to the lysosomes.
- Xintao Tu
- , Ting-Ting Chu
- & Nan Yan
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Article
| Open AccessDual roles and evolutionary implications of P26/poxin in antagonizing intracellular cGAS-STING and extracellular melanization immunity
Poxins or P26 have been identified as inhibitors of cGAS-STING mediated innate immunity. Here, the authors describe an independently evolved antiviral function of P26 in suppressing melanization, an insect immune response.
- Mengyi Yin
- , Wenhua Kuang
- & Manli Wang
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Article
| Open AccessTLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand
TLR3 plays a crucial role in anti-viral immune response by recognizing RNAs produced during virus infection. Here, the authors determine a high resolution structure of the activated cluster of TLR3. This structure will provide a platform for designing antiviral therapeutics and vaccines.
- Chan Seok Lim
- , Yoon Ha Jang
- & Jie-Oh Lee
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Article
| Open AccessCD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses
Modulation of metabolic pathways is linked to regulation of immune cells including macrophages. Here the authors identify a role for CD1d in the metabolic rewiring of macrophages, which alters responsiveness to innate stimuli.
- Phillip M. Brailey
- , Lauren Evans
- & Patricia Barral
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Article
| Open Accessvon Willebrand factor links primary hemostasis to innate immunity
von Willebrand factor (VWF) plays a critical role in primary hemostasis following vascular injury by tethering platelets to exposed collagen. Here, VWF binding to macrophages is shown to trigger NF-κB activation and induce pro-inflammatory responses.
- Clive Drakeford
- , Sonia Aguila
- & James S. O’Donnell
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Article
| Open AccessThe E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS
The activity and stability of the cytosolic DNA sensor cGAS, a key mediator of innate antiviral immunity and autoimmunity, is fine-tuned by post-translational modifications. Here, the authors demonstrate that the ubiquitin E3 ligase ARIH1 catalyzes the mono-ISGylation of cGAS and promotes its oligomerization in response to viral and self DNA.
- Tian-Chen Xiong
- , Ming-Cong Wei
- & Dandan Lin
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Article
| Open AccessDifferential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation
Responsive exocytosis in neutrophil leukocytes involves actin depolymerisation-dependent sequential release of gelatinase granules, then strongly pro-inflammatory azurophilic granules. Here authors show that the actin nucleator protein WASH facilitates the initial step of innate immune activation by gelatinase granules while inhibiting release of pro-inflammatory granules.
- Jennifer L. Johnson
- , Elsa Meneses-Salas
- & Sergio D. Catz
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Article
| Open AccessAdar-mediated A-to-I editing is required for embryonic patterning and innate immune response regulation in zebrafish
Additional roles for A-to-I editing of RNA continue to be uncovered. Niescierowicz et al. report prevalent A-to-I editing in the zebrafish transcriptome, and the distinct maternal and zygotic functions of the editing enzyme Adar in embryonic patterning and in the regulation of innate immune response, respectively.
- Katarzyna Niescierowicz
- , Leszek Pryszcz
- & Cecilia Winata
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Article
| Open AccessIFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses
The effect of IFITM3 on viral pathogenesis is poorly understood. Here, the authors show that IFITM3 restricts cytomegalovirus pathogenesis by reducing Nogo-B-mediated inflammation in response to viral stimuli.
- M. Clement
- , J. L. Forbester
- & I. R. Humphreys
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Article
| Open AccessSirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
Host defense against helminth infection is mediated by mucosal type 2 immunity. Using gain- and loss-of-function mouse models, and mouse intestinal organoids, Xiong et al. show that SIRT6 modulates tuft and goblet cell expansion in intestinal epithelium by activating STAT6 to maintain type 2 mucosal immunity in response to helminth infection.
- Xiwen Xiong
- , Chenyan Yang
- & Qingzhi Wang
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Article
| Open AccessThe nucleolus is the site for inflammatory RNA decay during infection
The nucleolus is the traditional site for ribosomal RNA biogenesis. Here, the authors find that the nucleolus is a site of inflammatory pre-mRNA turnover and elucidated how immune homeostasis can be maintained by controlling inflammatory gene expression.
- Taeyun A. Lee
- , Heonjong Han
- & Boyoun Park
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Article
| Open AccessStructure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti
Aedes aegypti can act as a vector for viral pathogens but the mechanism of viral resistance and evolving host-pathogen tolerance are poorly understood. Here the authors structurally characterise a duplicated pair of interacting Toll immunoreceptors and the cytokine ligand Spaetzle1C and show their dose-dependent function and mechanism of activation.
- Yoann Saucereau
- , Thomas H. Wilson
- & Monique Gangloff
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Article
| Open AccessEarly macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.
- L. Orliaguet
- , T. Ejlalmanesh
- & F. Alzaid
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Article
| Open AccessInvariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor
Trypanosomes evade the immune response through antigenic variation of a surface coat containing variant surface glycoproteins (VSG). They also express invariant surface glycoproteins (ISGs), which are less well understood. Here, Macleod et al. show that ISG65 of T. brucei is a receptor for complement component 3. They provide the crystal structure of T. brucei ISG65 in complex with complement C3d and show evidence that ISG65 is involved in reducing trypanosome susceptibility to C3-mediated clearance in vivo.
- Olivia J. S. Macleod
- , Alexander D. Cook
- & Mark Carrington
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Article
| Open AccessThe protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation
The anti-viral protein MAVS forms aggregates as part of the antiviral response and promoting type I IFN responses. Here the authors show that protein arginine methyltransferase 9 (PRMT9) methylates MAVS to keep the protein in a non-aggregated state and propose a regulatory mechanism for MAVS.
- Xuemei Bai
- , Chao Sui
- & Chengjiang Gao
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Article
| Open AccessPerforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism
Direct visualization of the structural transformation from pre-pore to pore of the mammalian immune defense complex perforin-2 (PFN2) reveals a clockwise hand-over-hand mechanism that propagates at ~15 subunits per second.
- Fang Jiao
- , François Dehez
- & Simon Scheuring
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Article
| Open AccessTranscription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes
The transcription factor IRF8 has been shown to regulate monocyte differentiation via its DNA-binding activity. Here authors show that IRF8 is also involved in cytosolic DNA sensing via its phosphorylation-dependent association to the adaptor protein STING, thus representing an important checkpoint between immune response and autoimmunity in monocytes.
- Wei-Wei Luo
- , Zhen Tong
- & Yan-Yi Wang
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Article
| Open AccessEGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance
In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.
- Shirong Cao
- , Yu Pan
- & Ming-Zhi Zhang