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| 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
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Article
| Open AccessIFN-γ stimulated murine and human neurons mount anti-parasitic defenses against the intracellular parasite Toxoplasma gondii
Toxoplasma gondii can persist in neurons in the central nervous system, presumably because neurons have limited cell-intrinsic immune responses. However, here, Chandrasekaran et al. show that IFN-gamma stimulated primary murine neurons can clear T. gondii and that IFN-gamma stimulated murine and human neurons show decreased infection rates.
- Sambamurthy Chandrasekaran
- , Joshua A. Kochanowsky
- & Anita A. Koshy
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Article
| Open AccessPathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling
Guanylate-binding proteins (GBP) have a function in inflammasome formation and pathogen defence. Here the authors show that these GBP proteins are able to kill certain bacteria and promote selective inflammasome activation and that this is mediated by specific GBP protein regions.
- Shouya Feng
- , Daniel Enosi Tuipulotu
- & Si Ming Man
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Article
| Open AccessStructural basis of human TREX1 DNA degradation and autoimmune disease
TREX1 is a cytosolic DNA nuclease and the genetic mutations of it are linked to autoimmune diseases. Here the authors determine the first structure of the human TREX1–DNA complex, and provide a new foundation to explain how patient TREX1 mutations cause autoimmune disease.
- Wen Zhou
- , Desmond Richmond-Buccola
- & Philip J. Kranzusch
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Article
| Open AccessNatural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
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Article
| Open AccessAtypical sideways recognition of CD1a by autoreactive γδ T cell receptors
T cell receptors are generally thought to contact antigens presented in an end to end configuration. Here the authors show a geometrically alternate sideways mode of recognition of the antigen-presenting molecule CD1a by a γδ T cell receptor.
- Marcin Wegrecki
- , Tonatiuh A. Ocampo
- & Jamie Rossjohn
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Article
| Open AccessA degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
- Hayden Weng Siong Tan
- , Guang Lu
- & Han-Ming Shen
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Article
| Open AccessInnate immune responses against the fungal pathogen Candida auris
Candida auris is a multidrug-resistant human fungal pathogen responsible for nosocomial outbreaks worldwide. Here, the authors identify differential innate immune responses induced by C. auris and Candida albicans in vitro and in vivo, which correlate with structural features of the cell wall.
- Yuanyuan Wang
- , Yun Zou
- & Dongsheng Zhou
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Article
| Open AccessMacrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes
The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.
- Catherine J. Greene
- , Jenny A. Nguyen
- & Robin M. Yates
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Article
| Open AccessTH17 cells promote CNS inflammation by sensing danger signals via Mincle
Mincle is a pattern recognition receptor that senses danger signals in innate immune cells. Here authors show in an experimental autoimmune encephalomyelitis mouse model that tissue damage triggers Mincle signaling on inflammatory helper T cells, leading to inflammasome-mediated IL-1β production and reinforced inflammation.
- Quanri Zhang
- , Weiwei Liu
- & Xiaoxia Li
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Article
| Open AccessDeficiency in coatomer complex I causes aberrant activation of STING signalling
Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.
- Annemarie Steiner
- , Katja Hrovat-Schaale
- & Seth L. Masters
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Article
| Open AccessMechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip
Mechanical forces in lungs facilitate breathing motions. Here the authors use a microfluidic human lung alveolus chip to study influenza infection and find that mechanical forces from active chips also induce innate inflammatory responses via, at least partially, signaling from TRPV4 and RAGE, thereby implicating them as potential therapeutic targets for lung inflammation.
- Haiqing Bai
- , Longlong Si
- & Donald E. Ingber
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Article
| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessLung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection
Smallpox is a highly contagious respiratory pathogen associated with a high mortality rate. Here the authors utilize a mouse model of intranasal vaccinia virus infection and show a C7 gene encoded virulence factor attenuates type I IFN release by lung type II alveolar epithelial cells and reduces lung inflammatory monocyte responses.
- Ning Yang
- , Joseph M. Luna
- & Liang Deng
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Article
| Open AccessPCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation
cGAS senses viral DNA and forms cytosolic cGAS-DNA granules to mediate anti-DNA viral signaling pathway. Here the authors show that PCBP2 interacts with cGAS and antagonizes condensation of cGAS-DNA granules, thus maintaining host immune homeostasis.
- Haiyan Gu
- , Jing Yang
- & Qinmiao Sun
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Article
| Open AccessS100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy
Defects in BRCA1, a gene involved in homologous recombination DNA repair, are common in triple negative breast cancer. Here the authors show that Brca1 deficiency in preclinical breast cancer models is associated with the accumulation of myeloid derived suppressive cells and resistance to immune checkpoint blockade, that could be overcome by targeting S100A9 and CXCL12.
- Jianjie Li
- , Xiaodong Shu
- & Xiaoling Xu
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Article
| Open AccessHuman rhinovirus promotes STING trafficking to replication organelles to promote viral replication
Evidence exists that the typically antiviral signaling mediator STING is, counterintuitively, needed for optimal human rhinovirus infection. Here the authors confirm this finding and show how human rhinovirus can reduce stored Ca2+ levels to drive this effect.
- Martha Triantafilou
- , Joshi Ramanjulu
- & Kathy Triantafilou
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Article
| Open AccessAutophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23
The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c+ cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.
- Lauriane Galle-Treger
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessIdentification and establishment of type IV interferon and the characterization of interferon-υ including its class II cytokine receptors IFN-υR1 and IL-10R2
Interferons are critical soluble components of the inflammatory process and are composed of three types with associated receptor complexes. Here the authors identify and characterise the type IV interferon, IFN-υ, and identify its associated receptors, denote functionality during in vivo infection and ascertain its genomic localisation.
- Shan Nan Chen
- , Zhen Gan
- & Pin Nie
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Article
| Open AccessTLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
The immunopathology of Duchenne Muscular Dystrophy includes a disturbed balance of pro and anti-inflammatory macrophages. Here the authors implicate trained innate immunity in a murine model of the disease, and reveal TLR4 as a key regulator of this process.
- Salyan Bhattarai
- , Qian Li
- & Basil J. Petrof
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Article
| Open AccessRe-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer
Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.
- Alok Kumar Singh
- , Monali Praharaj
- & Trinity J. Bivalacqua
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Article
| Open AccessEndothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation
In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.
- Qiang Zhao
- , Young-Min Han
- & Ming-Hui Zou
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Article
| Open AccessMyeloid cell interferon responses correlate with clearance of SARS-CoV-2
To gain insights into the early immune dynamics of transcriptional changes during SARS-CoV-2 infection, Singh et al. provide longitudinal scRNA-Seq of the broncho-alveolar compartment of SARS-CoV-2 infected rhesus macaques. They observe an accumulation of a distinct macrophage population that possesses an interferon-driven innate anti-viral gene signature early during infection that correlates with viral clearance.
- Dhiraj K. Singh
- , Ekaterina Aladyeva
- & Deepak Kaushal
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Article
| Open AccessMyeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7
The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.
- Lili Gu
- , David Casserly
- & Andrew G. Bowie
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Article
| Open AccessThe transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans
Intestinal immune responses to intracellular infection of Caenorhabditis elegans and other Invertebrate hosts are not well understood. Here the authors show a key role for the transcription factor ZIP-1 during intestinal intracellular infection.
- Vladimir Lažetić
- , Fengting Wu
- & Emily R. Troemel
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Article
| Open AccessDirectly recruited GATA6 + peritoneal cavity macrophages contribute to the repair of intestinal serosal injury
Upon intestinal injury, bone marrow derived monocytes are recruited to the damaged site through the bloodstream. Authors here show that peritoneal cavity macrophages directly migrate to the damaged intestine in an ATP and hyaluronan dependent manner, and participate in the restoration of tissue integrity.
- Masaki Honda
- , Masashi Kadohisa
- & Taizo Hibi
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Article
| Open AccessCross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators
Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.
- Friederike L. Pennemann
- , Assel Mussabekova
- & Andreas Pichlmair
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Article
| Open AccessNUDT2 initiates viral RNA degradation by removal of 5′-phosphates
RNA of some viruses is protected from degradation by a 5′ triphosphate group. Here the authors identify nudix hydrolase 2 (NUDT2) as novel antiviral defense protein that dephosphorylates viral RNA and thereby enables its degradation.
- Beatrice T. Laudenbach
- , Karsten Krey
- & Andreas Pichlmair
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Article
| Open AccessDefactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
The transcription factor, IRF5, has been implicated in the regulation of inflammation, but how IRF5 protein is activated is still unclear. Here the authors use inhibitor library screening, biochemical analyses and in vivo/ex vivo data to show that a protein tyrosine kinase, Pyk2, may be key for the activation of IRF5 in macrophages and inflammatory responses in the gut.
- Grigory Ryzhakov
- , Hannah Almuttaqi
- & Irina A. Udalova
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Article
| Open AccessMDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.
- Qin Yu
- , Alba Herrero del Valle
- & Yorgo Modis
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Article
| Open AccessTau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
- Meihua Jin
- , Hiroki Shiwaku
- & Hitoshi Okazawa
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Article
| Open AccessA non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is normally induced by innate immunity sensing for protection from pathogens. Here the authors show that cGAMP is also upstream of DNA damage signaling by activating ATM-CHK2-mediated repair pathway, while simultaneously suppressing the homology-directed repair.
- Daipayan Banerjee
- , Kurt Langberg
- & Nagaraj Kerur
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Article
| Open AccessCleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors
Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling.
- Amanda L. Gavin
- , Deli Huang
- & David Nemazee
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Article
| Open AccessCD127+ CD94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with Crohn’s disease
Phenotypic markers that overlap between ILC1 and NK populations have impacted the robust and specific analysis of these immune cell populations. Employing scRNA sequencing here the authors identify CD127+ CD94+ innate lymphoid cells that express granulysin and perforin and are expanded in patients with Crohn’s disease.
- L. Krabbendam
- , B. A. Heesters
- & H. Spits
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Article
| Open AccessNLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly
Nlrp3 inflammasome activation requires Nek7 recruitment to drive ASC speck formation. Here the authors show how Nlrp3 phosphorylation events control this Nek7 recruitment.
- Tingting Niu
- , Charlotte De Rosny
- & Bénédicte F. Py
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Article
| Open AccessListeria exploits IFITM3 to suppress antibacterial activity in phagocytes
Interferon (IFN) is an important component of antiviral immunity, but can also be exploited by bacteria for immune evasion. Here the authors show that Listeria monocytogenes (Lm) induces type I IFN to suppress the degradation of Lm virulence proteins, ActA and LLO, and promote Lm infection in an IFITM3-dependent manner, thereby hinting at a potential target for antimicrobial therapy.
- Joel M. J. Tan
- , Monica E. Garner
- & John H. Brumell
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Article
| Open AccessGenotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways
The cytidine deaminase APOBEC3A is a main source of mutagenesis in many types of cancer. Here the authors reveal that transient up-regulation of APOBEC3A and other pro-inflammatory genes can occur due to viral infection and genotoxic stress via multiple pathways.
- Sunwoo Oh
- , Elodie Bournique
- & Rémi Buisson
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Article
| Open AccessTemporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19
The immune response is key in determining disease severity of COVID19. Here Nouailles et al., apply bulk proteomics and scRNA-Seq of lung and blood samples of SARS-CoV-2 infected Syrian hamsters and provide a temporal atlas of the systemic and pulmonary cellular responses.
- Geraldine Nouailles
- , Emanuel Wyler
- & Martin Witzenrath
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Article
| Open AccessTRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation
Post-translational modifications are important regulators of NLRP3 inflammasome activity. Here the authors show that the E3 ligase TRIM28 can SUMOylate NLRP3, thereby limiting its proteasomal degradation and increasing NLRP3 inflammasome activity.
- Ying Qin
- , Qi Li
- & Wei Zhao