A5034570392- Immune Response and Inflammation
- Immune Cell Function and Interaction
- NF-κB Signaling Pathways
- T-cell and B-cell Immunology
- interferon and immune responses
- RNA modifications and cancer
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Pancreatic function and diabetes
- RNA and protein synthesis mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Retinal Diseases and Treatments
- Immunotherapy and Immune Responses
- RNA regulation and disease
- Single-cell and spatial transcriptomics
- Molecular Biology Techniques and Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Cancer Immunotherapy and Biomarkers
- Diabetes and associated disorders
- Galectins and Cancer Biology
- Nutrition, Genetics, and Disease
- Chronic Myeloid Leukemia Treatments
- Genomics and Rare Diseases
The University of Texas Southwestern Medical Center
2015-2024
Southwestern Medical Center
2013-2023
Fondazione IRCCS Istituto Nazionale dei Tumori
2023
Scripps Research Institute
2007-2012
Yale University
2003-2006
Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body content. Several proteins induce expression hepcidin-encoding gene Hamp in response to infection or high levels iron. However, mechanism(s) suppression during depletion are poorly understood. We describe mask: recessive, chemically induced mutant mouse phenotype, characterized by progressive loss (but not facial) hair and microcytic anemia. The mask phenotype results from reduced absorption...
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...
Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T help. We report that immunization these cell–independent type 2 (TI-2) antigens causes up-regulation endogenous retrovirus (ERV) RNAs antigen-specific mouse cells. These are detected via a mitochondrial antiviral signaling protein (MAVS)–dependent RNA sensing pathway or reverse-transcribed...
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...
Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response leads translation repression. This is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) protect them from cleavage the ribonuclease angiogenin. cell-specific SLFN2 deficiency results accumulation tRNA fragments, inhibit promote stress-granule formation....
Dendrite arbor structure is a critical determinant of nervous system function that must be actively maintained throughout life, but the signaling pathways regulate dendrite maintenance are essentially unknown. We report Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases required for cortical dendrites in mouse brain. arg - / initially develop normally indistinguishable from wild-type at postnatal day 21. branches not efficiently neurons, leading to reduction size by early...
A recessive phenotype called spin (spontaneous inflammation) was induced by N -ethyl- -nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, antichromatin antibodies. They are immunocompetent show enhanced resistance to infection Listeria monocytogenes . TLR-induced TNF IL-1 production normal macrophages derived from The autoinflammatory of mice is fully suppressed compound homozygosity for Myd88 poc ,...
Regulatory T (T(reg)) cells expressing forkhead box P3 (Foxp3) arise during thymic selection among thymocytes with modestly self-reactive cell receptors. In vitro studies suggest Foxp3 can also be induced peripheral CD4(+) in a cytokine dependent manner. T(reg) of or origin may serve different functions vivo, but both populations are phenotypically indistinguishable wild-type mice. Here we show that mice Carma1 point mutation lack CD4(+)Foxp3(+) and demonstrate cell-intrinsic requirement for...
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...
Diprovocim is a recently discovered exceptionally potent, synthetic small molecule agonist of TLR2/TLR1 and has shown significant adjuvant activity in anticancer vaccination against murine melanoma. Since bears no structural similarity to the canonical lipopeptide ligands TLR2/TLR1, we investigated how interacts with through vitro biophysical, structural, computational approaches. We found that induced formation heterodimers as well TLR2 homodimers vitro. determined crystal structure complex...
Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) complex, innate immune for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4-MD-2 activation by ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here...
In a genetic screen, we identified two viable missense alleles of the essential gene Midnolin (Midn) that were associated with reductions in peripheral B cells. Causation was confirmed mice targeted deletion four six MIDN protein isoforms. expressed predominantly lymphocytes where it augmented proteasome activity. We showed purified directly stimulated 26S activity vitro manner dependent on ubiquitin-like domain and C-terminal region. MIDN-deficient cells displayed aberrant activation...
Deficiencies of subunits the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study its physiological function. Here we describe a missense mutation Med30 causing progressive cardiomyopathy homozygous mice that, although viable during lactation, show precipitous lethality 2–3 wk after weaning. Expression profiling reveals pleiotropic changes transcription cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning...
Significance Immunoglobulins exist in several forms, or isotypes, that carry out distinct effector functions. During an antibody response, B cells can switch their immunoglobulin isotype through the process of class-switch recombination (CSR). CSR to IgD is a rare event compared with other and its regulation poorly understood. Here we report mice lacking DNA damage-response protein 53BP1 display hyper-IgD syndrome despite deficiencies classes. By studying these mice, discovered mutant...
Precise control of Wnt signaling is necessary for immune system development. In this study, we detected severely impaired development all lymphoid lineages in mice, resulting from an N-ethyl-N-nitrosourea-induced mutation the limb region 1-like gene (Lmbr1l), which encodes a membrane-spanning protein with no previously described function immunity. The interaction LMBR1L glycoprotein 78 (GP78) and ubiquitin-associated domain-containing 2 (UBAC2) attenuated lymphocytes by preventing maturation...
Computational inference of mutation effects is necessary for genetic studies in which many mutations must be considered as etiologic candidates. Programs such PolyPhen-2 predict the relative severity damage caused by missense mutations, but not actual probability that a will reduce/eliminate protein function. Based on genotype and phenotype data 116,330 ENU-induced Mutagenetix database, we calculate putative null PolyPhen-2-classified "probably damaging", "possibly or benign" have,...
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...
The protein midnolin (MIDN) augments proteasome activity in lymphocytes, where it is predominantly expressed adult mice. MIDN binds both to proteasomes and substrates, but the mechanism by which facilitates substrate degradation a ubiquitin-independent manner unknown. Here, we present cryo-electron microscopy structures of substrate-engaged, MIDN-bound human two conformational states. induces conformations similarly ubiquitinated substrates using its ubiquitin-like domain bind deubiquitinase...
We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of chemically induced mutation responsible for neurobehavioral phenotype. Mice homozygous missense in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration the organ Corti. Consistent with this phenotype, COMT2 is highly expressed sensory hair cells inner ear. enzymatic activity significantly reduced by mutation,...