A5110206804- Immune Response and Inflammation
- Immune Cell Function and Interaction
- NF-κB Signaling Pathways
- Inflammasome and immune disorders
- interferon and immune responses
- CRISPR and Genetic Engineering
- Cancer Immunotherapy and Biomarkers
- T-cell and B-cell Immunology
- Single-cell and spatial transcriptomics
- IL-33, ST2, and ILC Pathways
- Heme Oxygenase-1 and Carbon Monoxide
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Photosynthetic Processes and Mechanisms
- Immunodeficiency and Autoimmune Disorders
- Cytokine Signaling Pathways and Interactions
- Evolution and Genetic Dynamics
- Cell death mechanisms and regulation
- vaccines and immunoinformatics approaches
- Plant Reproductive Biology
- Autoimmune and Inflammatory Disorders Research
- Peptidase Inhibition and Analysis
- Genetics, Aging, and Longevity in Model Organisms
- Macrophage Migration Inhibitory Factor
- Respiratory viral infections research
The University of Texas Southwestern Medical Center
2012-2024
Center for Excellence in Molecular Cell Science
2006-2008
Chinese Academy of Sciences
2006-2008
Shanghai Institutes for Biological Sciences
2006-2008
University of Chinese Academy of Sciences
2007
Tsinghua University
2006
Significance The Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex recognizes lipopolysaccharide (LPS) on Gram-negative bacteria to induce an innate immune response. Neoseptins, chemically synthesized peptidomimetics that bind and activate the mouse TLR4 (mTLR4)/MD-2 independent of LPS, were discovered through unbiased screening reverse genetic studies, improved by chemical modification. NMR X-ray crystallography TLR4/MD-2/Neoseptin-3 determined mechanism which...
Significance Adjuvants enhance adaptive immune responses, sometimes through unknown mechanisms, and can be used to augment both humoral cellular responses cancer antigens. We report the immunological effects of synthetic chemical adjuvant Diprovocim, which targets innate receptor TLR1/TLR2 in mice humans. Diprovocim displayed strong activity mice, particularly abetting responses. Immunization against a genetically engineered tumor-specific antigen, ovalbumin, when adjuvanted with inhibited...
With the wide availability of massively parallel sequencing technologies, genetic mapping has become rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification N-ethyl-N-nitrosourea-induced mutations that cause phenotypes mice. All are identified by whole exome G1 progenitor and their zygosity is established G2/G3 mice before phenotypic assessment. Quantitative qualitative traits, including lethal effects, single or multiple combined pedigrees...
Interferon regulatory factor 3 (IRF3) plays a crucial role in mediating cellular responses to virus intrusion. The protein kinase TBK1 is key regulator inducing phosphorylation of IRF3. mechanisms during IRF3 activation remain poorly characterized. In the present study, we have identified by yeast two-hybrid approach specific interaction between and chaperone heat-shock 90 kDa (Hsp90). C-terminal truncation mutant Hsp90 strong dominant-negative inhibitor activation. Knockdown endogenous RNA...
A screen conducted with nearly 100000 compounds and a surrogate functional assay for stimulation of an immune response that measured the release TNF-α from treated human THP-1 myeloid cells differentiated along macrophage line led to discovery diprovocims. Unique these efforts special interest, screening leads this new class activators came compound library designed promote cell-surface receptor dimerization. Subsequent comprehensive structure–activity relationship studies improved potency...
The role of lipids in inflammasome activation remains underappreciated. phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein–coupled seven-transmembrane receptor (PAFR). PAF is associated with number inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function be fully elucidated. We show that isoforms and PAF-like can activate inflammasome, resulting IL-1β IL-18 maturation. This dependent on NLRP3,...
Abstract Many immune responses depend upon activation of NF-κB, an important transcription factor in the elicitation a cytokine response. Here we show that N4BP1 inhibits TLR-dependent NF-κB by interacting with signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO–NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like conjugation ER degradation-like) domains mediate interaction NEMO COZI domain. Both vitro mice, N4bp1...
As a latent transcription factor, nuclear factor κB (NF-κB) translocates from the cytoplasm into nucleus upon stimulation and mediates expression of genes that are important in immunity, inflammation, development. However, little is known about how it regulated inside nucleus. By two-hybrid approach, we identify prefoldin-like protein, ubiquitously expressed transcript (UXT), predominantly interacts specifically with NF-κB RNA interference knockdown UXT leads to impaired activity...
The NLRP3 (NLR family, Pyrin domain containing 3) inflammasome is a multiprotein complex comprised of NLRP3, pro-caspase-1, the adaptor protein apoptosis-associated speck-like CARD (ASC), and kinase NIMA related 7 (NEK7) (Shi et al., 2016; He Schmid-Burgk 2016). When cells are exposed to microbes and/or danger signals, assembles serves as platform for activation caspase-1. Caspase-1 promotes processing secretion pro-inflammatory cytokines interleukin-1β (IL-1β), IL-18, IL-33 well pyroptosis...
Abstract Exhibiting rapid polarized growth, the pollen tube delivers male gametes into ovule for fertilization in higher plants. To get an overall picture of gene expression during germination and we profiled transcription patterns 1,536 cDNAs from lily (Lilium longiflorum) by microarray. Among those that exhibited significant differential expression, a cDNA named ankyrin repeat-containing protein (LlANK) was thoroughly studied. The full-length LlANK sequence predicts containing five tandem...
Significance IBD is one of the most common early manifestations LRBA deficiency and has been attributed to impaired regulatory T cell function. However, whether other immune types also contribute not comprehensively tested. We found that, in LRBA-deficient mice, DCs significantly colitis DSS model. showed that blocking innate signaling from endosomal TLRs, TLR3, TLR7, TLR9, Lrba −/− mice dramatically reduced their susceptibility DSS-induced colitis. Our data indicate a role for limiting TLR...
Abstract Signals emanating from the T-cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 fate. Understanding how these signals respond to homeostatic microenvironmental cues can reveal new ways therapeutically direct function. Through forward genetic screening in mice, we discover that loss-of-function mutations LDL receptor-related protein 10 ( Lrp10 ) cause naive central memory T cells accumulate peripheral lymphoid organs. encodes a conserved cell...
Significance We developed software called Candidate Explorer (CE) that uses a machine-learning algorithm to identify chemically induced mutations are causative of screened phenotypes. CE determines the probability mutation will be verified as for phenotype if gene is independently targeted knockout or recreation mutation. 67 parameters from mapping data—including gene, mutation, genotype, allelism, and information—to determine Score verification probability. used evaluate ∼87,000...
The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR act through well-defined mechanism (TLR1/TLR2 agonist), exhibit exquisite structure–activity relationships, and display in vivo adjuvant activity. They possess potent efficacious agonist activity toward human TLR1/TLR2 but modest agonism the murine receptor. A manner by which diprovocims can be functionalized without impacting hTLR1/TLR2 is detailed, permitting future linkage antigenic,...
In mice, adenovirus (Ad)-elicited IFN-ab mediates the overproduction of LPS stimulated cytokines such as TNFa and IL-6. We found that Ad infection also itself enables its production in splenic marginal zone macrophages, which don’t produce response to alone. show importance scavenger receptor MARCO for uptake cytokine vivo, differential contribution rIFN-b LPS-induced macrophage subsets. TNF-a IL-6 responses are enhanced alveolar macrophages macrophage-like lines, but downregulated...
Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen C57BL/6J mice, we discovered mutation host H2-Aa that caused strong immune-mediated resistance mouse melanomas. encodes an MHC class II α chain, and its absence mice eliminates all MHC-II expression. deficiency, specifically dendritic cells (DC), led quantitative increase type 2 conventional DC (cDC2) decrease cDC1. H2-Aa-deficient cDC2, not...
Abstract Many immune responses depend upon activation of NF-κB, a key transcription factor in the elicitation cytokine response. Here we demonstrate that N4BP1 inhibited TLR-dependent NF-κB by interacting with signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like conjugation ER degradation) domains mediated interaction NEMO COZI domain. Both vitro mice, N4bp1 deficiency...
SUMMARY Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 fate. Understanding how these signals respond to homeostatic microenvironmental cues can reveal new ways therapeutically direct function. Through forward genetic screening in mice, we discovered that loss-of-function mutations LDL related protein 10 ( Lrp10 ) caused naïve central memory cells accumulate peripheral lymphoid organs. encodes a conserved surface of...
Abstract Agonists and antagonists of Toll-like receptors (TLRs) may be useful as vaccine adjuvants or suppressors inflammation, respectively. In an effort to identify compounds capable activating macrophages via TLRs other sensors, a synthetic compound library was screened using mouse peritoneal human THP-1 cells. Through extensive SAR studies initial hits, we developed two strong agonists: Neoseptin-3 Diprovocim. Genetic established that neoseptin-3 is TLR4/MD-2 agonist with no structural...
Abstract When applied to immunity, forward genetic studies use meiotic mapping provide strong statistical evidence that a particular mutation is causative of immune phenotype. Notwithstanding this, co-segregation multiple mutations, occasional unawareness and paucity homozygotes may lead erroneous declarations cause effect. We sought improve the selection authentic mutations using machine learning software tool, Candidate Explorer (CE), which integrates 65 data features into single numeric...