A5054036200- interferon and immune responses
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- SARS-CoV-2 and COVID-19 Research
- Cellular transport and secretion
- Ubiquitin and proteasome pathways
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- Protein Degradation and Inhibitors
- T-cell and B-cell Immunology
- vaccines and immunoinformatics approaches
- Neuroscience and Neuropharmacology Research
- Hematopoietic Stem Cell Transplantation
- Animal Virus Infections Studies
- HIV Research and Treatment
- Respiratory viral infections research
- Biochemical and Structural Characterization
- Immune Cell Function and Interaction
- Prion Diseases and Protein Misfolding
- RNA Interference and Gene Delivery
- Tryptophan and brain disorders
- Viral Infections and Immunology Research
- CAR-T cell therapy research
- Cell Adhesion Molecules Research
MRC Laboratory of Molecular Biology
2013-2024
Medical Research Council
2008-2023
Osaka University
2018
Stanford University
1994-1995
Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer tau misfolding (seeding) as mechanism spread within an affected brain, a process reminiscent viral infection. However, whereas microbial pathogens can be recognized nonself by immune receptors, misfolded assemblies evade detection, they host-derived. Here, we show that when enter cell, detected...
TRIM5 is a RING domain E3 ubiquitin ligase with potent antiretroviral function. assembles into hexagonal lattice on retroviral capsids, causing envelopment of the infectious core. Concomitantly, initiates innate immune signaling and orchestrates disassembly viral particle, yet how these antiviral responses are regulated by capsid recognition unclear. We show that assembly triggers N-terminal polyubiquitination collectively drives responses. In uninfected cells, monoubiquitination...
Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection of viral before replication. TRIM21 triggers an initial wave cytokine transcription antibody, rather than pathogen, driven. This early response augmented second transcriptional program, determined nature...
HIV-1 hijacks host proteins to promote infection. Here we show that HIV is also dependent upon the metabolite inositol hexakisphosphate (IP6) for viral production and primary cell replication. recruits IP6 into virions using two lysine rings in its immature hexamers. Mutation of either ring inhibits packaging reduces production. Loss results with highly unstable capsids, leading a profound loss reverse transcription Replacement one hydrophobic isoleucine core restores production, but...
Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but mechanisms Ab protection incompletely understood. In this work, we used a variety cell and animal model systems showed that cytosolic receptor E3 ligase TRIM21 (T21) could play role against pathology. Tau-Ab complexes were internalized cytosol neurons, which enabled T21 engagement seeded aggregation. Ab-mediated pathology was...
Selective degradation of pathological protein aggregates while sparing monomeric forms is major therapeutic interest. The E3 ligase tripartite motif–containing 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement TRIM21 RING domain clustering for activation, yet effective targeting intracellular assemblies remains challenging. Here, we fused a target-specific nanobody create intracellularly expressed constructs capable selectively degrading...
Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show tripartite-motif protein 21 (TRIM21), ubiquitously expressed E3 ubiquitin ligase targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type rapidly up-regulate and control viremia. Trim21 heterozygous...
Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via cytosolic antibody receptor TRIM21, but how this is regulated unknown. Here we show that TRIM21 constitutively repressed by its B-Box domain activated phosphorylation. The occupies an E2 binding site on catalytic RING mimicking E2-E3 interactions, inhibiting ubiquitination preventing activation. derepressed IKKβ TBK1...
Article1 December 2020Open Access Source DataTransparent process Viral nucleoprotein antibodies activate TRIM21 and induce T cell immunity Sarah L Caddy Corresponding Author [email protected] orcid.org/0000-0002-9790-7420 MRC Laboratory of Molecular Biology, Cambridge, UK CITIID, Department Medicine, University Search for more papers by this author Marina Vaysburd Guido Papa Mark Wing Kevin O'Connell Diana Stoycheva Institute Microbiology, ETH Zurich, Switzerland Stian Foss Immunology, Oslo...
Rotavirus is a major cause of gastroenteritis in children, with infection typically inducing high levels protective antibodies. Antibodies targeting the middle capsid protein VP6 are particularly abundant, and as only exposed inside cells, neutralisation must be post-entry. However, while system poly immune globulin receptor (pIgR) transcytosis has been proposed for anti-VP6 IgAs, mechanism by which VP6-specific IgG mediates protection remains less clear. We have developed an intracellular...
Assemblies of tau can transit between neurons, seeding aggregation in a prion-like manner. To accomplish this, must cross cell-limiting membranes, process that is poorly understood. Here, we establish assays for the study entry into cytosol as phenomenon distinct from uptake, real time, and at physiological concentrations. The pathway cell type specific and, highly sensitive to cholesterol. Depletion cholesterol transporter Niemann-Pick C1 or extraction membrane renders neurons permissive...
Abstract HIV‐1 uses inositol hexakisphosphate (IP6) to build a metastable capsid capable of delivering its genome into the host nucleus. Here, we show that viruses are unable package IP6 lack protection and detected by innate immunity, resulting in activation an antiviral state inhibits infection. Disrupting enrichment results defective capsids trigger cytokine chemokine responses during infection both primary macrophages T‐cell lines. Restoring with single mutation rescues ability infect...
Abstract INTRODUCTION Signatures of a type‐I interferon (IFN‐I) response are observed in the post mortem brain Alzheimer's disease (AD) and other tauopathies. However, effect IFN‐I on pathological tau accumulation remains unclear. METHODS We examined effects signaling primary neural culture models seeded aggregation P301S‐tau transgenic mouse context genetic deletion receptor (IFNAR). RESULTS Polyinosinic:polycytidylic acid (PolyI:C), synthetic analog viral nucleic acids, evoked potent...
Significance Viral-based delivery vectors have huge potential in the treatment of human disease. Adenoviral specifically proven highly efficacious delivering corrected genes, as part gene therapy, and vaccine epitopes for treating cancer infectious A principal obstacle to their widespread use is that antibodies potently neutralize them, limiting naïve patients. How block adenovirus-based transduction has long remained a mystery because, even though they prevent transgene expression, do not...
COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines drug-like advantages both. Bicycles are entropically constrained peptides stabilized by central chemical scaffold into bi-cyclic structure. Rapid screening diverse bacteriophage libraries against Spike yielded unique Bicycle binders across entire protein. Exploiting Bicycles' inherent combinability, converted...
Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro-inflammatory cell death. However, pathogens have evolved strategies to evade this autonomous system. Here, we show how antibodies combine sensors in primary human macrophages detect viral infection and activate the inflammasome. Our data demonstrate antibody opsonisation of virions can multiple ways. In first, binding adenovirus causes lysosomal damage, activating NLRP3 drive inflammasome...
The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. Here, we show that ferritin-like Dps from hyperthermophilic Sulfolobus islandicus, covalently coupled with antigens via SpyCatcher system, forms stable multivalent dodecameric vaccine nanoparticles remain intact even after lyophilisation. Immunisation experiments in mice demonstrated receptor binding domain (RBD) to (RBD-S-Dps) elicited higher antibody titre and an enhanced neutralising...
Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show TRIM21 potently inhibits the spreading infection of replicating cytopathic virus and activates innate immunity. We used quantitative PCR (qPCR)-based assay to measure in vitro replication mouse adenovirus type 1 (MAV-1), causes dose-dependent hemorrhagic encephalitis mice. Using this assay, genetic ablation or chemical inhibition...
Macrocyclic peptides are potentially a source of powerful drugs, but their de novo discovery remains challenging. Here we describe the high-affinity (Kd = 10 nM) peptide macrocycle (M21) against human tumor necrosis factor-alpha (hTNFα), key drug target in treatment inflammatory disorders, directly from diverse semi-synthetic phage repertoires. The bicyclic M21 (ACPPCLWQVLC) comprises two loops covalently anchored to 2,4,6-trimethyl-mesitylene core and upon binding induces disassembly...
The humoral immune response to SARS-CoV-2 results in antibodies against spike (S) and nucleoprotein (N). However, whilst there are widely available neutralization assays for S antibodies, is no assay N-antibody activity. Here, we present a simple vitro method called EDNA (electroporated-antibody-dependent assay) that provides quantitative measure of activity unpurified serum from convalescents. We show N neutralize intracellularly cell-autonomously but require the cytosolic Fc receptor...
Abstract Activation of T cells leading to graft-vs-host disease (GVHD) requires two signaling events: the Ag-specific signal generated through engagement TCR/CD3 complex with antigenic peptide fragments presented by MHC molecules on APCs and second provided additional costimulatory ligands. have preferential requirements depending their state activation-induced maturation. In present study, we investigated role receptor-ligand pair VLA-4 (alpha 4 beta 1) VCAM-1 in allogeneic cell responses...
Abstract A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result collective action. Assemblies the protein tau can exhibit seeding behaviour, potentially underlying apparent spread aggregation in many neurodegenerative diseases. Here we ask whether assemblies share with classical pathogens characteristic behaviour. We used organotypic hippocampal slice cultures P301S transgenic mice order to...