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Structural 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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| Open Access
Natural 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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| Open Access
Atypical 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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A 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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Innate 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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Macrophages 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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| Open Access
TH17 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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Deficiency 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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Mechanical 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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| Open Access
Phagosomal 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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Lung 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 Access
PCBP2 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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S100A9-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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Human 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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| Open Access
Autophagy 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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Identification 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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TLR4 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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Re-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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Endothelial 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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| Open Access
Myeloid 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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| Open Access
Myeloid 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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The 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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Directly 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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Cross-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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NUDT2 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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| Open Access
Defactinib 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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MDA5 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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| Open Access
Tau 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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A 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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Cleavage 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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| Open Access
CD127+ 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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| Open Access
NLRP3 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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| Open Access
Listeria 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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Genotoxic 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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Temporal 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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TRIM28 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
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| Open Access
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
SAMHD1 is a cellular dNTPase proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting dNTP substrate supply; its anti-viral but not dNTPase function is downregulated by phosphorylation of T592. Here, Martinat et al. describe an additional SUMOylation at residue K595, which promotes the dNTPase-independent restriction activity.
- Charlotte Martinat
- , Arthur Cormier
- & Alessia Zamborlini
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| Open Access
IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro
IFITM proteins can inhibit several viruses, but effects on SARS-CoV-2 infection are not well understood. Here, the authors show that endogenous IFITMs support SARS-CoV-2 infection in different in vitro models by binding spike and enhancing virus entry.
- Caterina Prelli Bozzo
- , Rayhane Nchioua
- & Frank Kirchhoff
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| Open Access
Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease
IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.
- Tatsuma Ban
- , Masako Kikuchi
- & Tomohiko Tamura
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Article
| Open Access
Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Yi Yang
- , Adam Csakai
- & Hang Yin
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Article
| Open Access
Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response
Lipid droplets (LDs) are recognized as dynamic organelles and scaffolding platforms to regulate signalling cascades. Here, Monson et al. provide evidence that LDs are involved in regulation of an early antiviral immune response specifically through the enhanced modulation of IFN following viral infection in vitro and in vivo.
- E. A. Monson
- , K. M. Crosse
- & K. J. Helbig
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| Open Access
Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation
Terminal uridyltransferase 7 (TUT7) adds U-tails on diverse RNAs to promote degradation. Here the authors show that TUT7 is induced upon LPS treatment in macrophages and promotes decay of Regnase-1, thereby regulating the expression of a subset of cytokines, including IL-6.
- Chia-Ching Lin
- , Yi-Ru Shen
- & Li-Chung Hsu
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| Open Access
Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils
The human voltage-gated proton channel (hHv1) maintains intracellular pH and membrane potential in sperm and neutrophils. Here, the authors show that albumin activates hHv1, by binding to the channel voltage sensor domains to enhance open probability and increases proton current, and that activation is required to trigger sperm to allow oocyte fertilization and to sustain production and release of immune inflammatory mediators during the neutrophil respiratory burst.
- Ruiming Zhao
- , Hui Dai
- & Steve A. N. Goldstein
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| Open Access
Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus
Serum Amyloid P is a humoral component with established roles in the response to bacterial infection and regulation of tissue remodeling. Here the authors provide evidence to a further crucial role of serum amyloid P in the context of fungal pathogen Aspergillus fumigatus.
- Andrea Doni
- , Raffaella Parente
- & Alberto Mantovani
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| Open Access
Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages
Here, using proteomics and cell-based assays, the authors show that HIV accessory protein Vpr mediates the degradation of host lysosomal-associated transmembrane protein 5 (LAPTM5) in monocyte-derived macrophages (MDM) to enhance infection in macrophages.
- Li Zhao
- , Shumei Wang
- & Guoxin Liang
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| Open Access
Structural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities
Yeast form part of the host microbiome with known impact on host immunity. Here the authors identify and investigate the impact of commensal yeast-derived polysaccharides in modulating host inflammation, and show its potential for inhibiting inflammation in a number of models of inflammatory diseases.
- Changhon Lee
- , Ravi Verma
- & Sin-Hyeog Im
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| Open Access
TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection
Innate immune cells respond to a number of environmental cues including TLR signalling. Here the authors implicate mechanical sensor Piezo1 in the TLR4 mediated host response to bacterial infection and implicate it in the enhancement of macrophage mediated host response.
- Jing Geng
- , Yiran Shi
- & Dawang Zhou
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Article
| Open Access
Tumor suppressor p53 regulates intestinal type 2 immunity
P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.
- Chun-Yuan Chang
- , Jianming Wang
- & Wenwei Hu
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| Open Access
USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS
Ubiquitination has an important function in the regulation of antiviral immunity involving the signalling molecule MAVS. Here the authors investigate deubiquitinating enzymes and show USP18 regulates MAVS mediated antiviral signalling through modulating the ubiquitination of MAVS via promotion of interaction between MAVS and TRIM31.
- Jinxiu Hou
- , Lulu Han
- & Chengjiang Gao
Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling