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  • 1
    Online Resource
    Online Resource
    Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 379, No. 6637 ( 2023-03-17)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6637 ( 2023-03-17)
    Abstract: Autoimmune diseases such as ankylosing spondylitis (AS) can be caused by emerging neoantigens that break immune tolerance in humans. Posttranslational modifications (PTMs) have been shown to be a critical mechanism that alters protein structure and function to generate neoantigens and induce subsequent autoimmune responses. Previous studies have confirmed that citrulline-modified peptides are a critical source of neoantigens in rheumatoid arthritis. However, the molecular mechanisms underlying neoantigen formation and pathogenic autoreactive responses for AS are largely unknown. There is an urgent need to develop a systematic approach to profiling the possible PTMs in patients with AS and identifying AS-associated PTMs responsible for autoreactive neoantigen production to better understand the etiology of autoimmune diseases. RATIONALE AS has been suggested to be an autoimmune disease because of its clear correlation with certain major histocompatibility complex (MHC) alleles, including HLA-B27. Neoantigens have been hypothesized to induce an aberrant immune response, leading to pathogenic autoreactive T cell responses and autoantibody generation in AS. Here, we developed a systematic open search approach to identify any possible amino acid residues and derivatives in the proteins that are different from the genomic coding sequences. We then applied this information to identify AS-related neoantigens with PTMs within a possible pool of PTM autoantigens and elucidate the pathogenesis of AS. RESULTS An open search approach was applied to identify any possible amino acid derivatives across the proteome of patients with AS. This approach generated a large set of noncoded amino acids representing the mass differences between the coded amino acids and actual residues. Among these, an amino acid derivative with a delta mass of 72.021 showed the greatest increase in patients with AS and resulted from a PTM called cysteine carboxyethylation. In vitro and in vivo experiments demonstrated that carboxyethylation at a cysteine residue of integrin αIIb [ITGA2B (CD41)] was catalyzed by cystathionine beta synthase (CBS) in a process that required 3-hydroxypropionic acid (3-HPA), a metabolite commonly released from gut microbes. Cysteine carboxyethylation induced the lysosomal degradation of ITGA2B and produced neoantigens that triggered MHC-II–dependent CD4 + T cell responses. Fluorescence polarization and enzyme-linked immunosorbent assay (ELISA) demonstrated that the identified carboxyethylated peptide (ITGA2B-ceC96) specifically interacted with HLA-DRA*01/HLA-DRB1*04 and was associated with autoantibody production and T cell responses in HLA-DRB1*04 patients. Additional in vitro assays showed that the neoantigen ITGA2B-ceC96 correlated with 3-HPA levels but was independent of CBS expression. HLA-DRB1 haplotype, the carboxyethylated peptide, specific autoantibodies, and 3-HPA levels in patients with AS all correlated with one another. 3-HPA–treated and ITGA2B-ceC96–immunized HLA-DR4 transgenic mice developed colitis and vertebral bone erosion. Thus, cysteine carboxyethylation induced by the metabolite 3-HPA generates a neoantigen that appears to be critical for autoimmune responses in patients with AS. CONCLUSION Cysteine carboxyethylation is an in vivo protein modification induced by the metabolite 3-HPA, which is commonly released from gut microbes. Carboxyethylated ITGA2B then induces autoantibody production and autoimmune response in AS. Our work provides a systematic workflow to identify differentially modified proteins that are important for neoantigen production in immune disorders. This approach furthers our understanding of AS pathogenesis and may aid in the development of neoantigen-based diagnosis and treatment for AS and other autoimmune diseases. Metabolite-induced cysteine carboxyethylation provokes HLA-restricted autoimmune responses in ankylosing spondylitis. 3-HPA, which is commonly obtained from food and gut microbes, induces carboxyethylation of cysteine residues in integrin αIIb (ITGA2B). Cysteine carboxyethylation requires CBS, and carboxyethylated ITGA2B (ITGA2B-ceC96) peptides are recruited to the HLA-DR4 complex and thereby stimulate CD4 + T cell responses closely related to AS.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg2482
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome
    Society for Neuroscience ; 2020
    In:  The Journal of Neuroscience Vol. 40, No. 6 ( 2020-02-05), p. 1355-1365
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 40, No. 6 ( 2020-02-05), p. 1355-1365
    Abstract: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, resulted from the silencing of the Fmr1 gene and the subsequent loss of fragile X mental retardation protein (FMRP). Spine dysgenesis and cognitive impairment have been extensively characterized in FXS; however, the underlying mechanism remains poorly understood. As an important regulator of spine maturation, intercellular adhesion molecule 5 (ICAM5) mRNA may be one of the targets of FMRP and involved in cognitive impairment in FXS. Here we show that in Fmr1 KO male mice, ICAM5 was excessively expressed during the late developmental stage, and its expression was negatively correlated with the expression of FMRP and positively related with the morphological abnormalities of dendritic spines. While in vitro reduction of ICAM5 normalized dendritic spine abnormalities in Fmr1 KO neurons, and in vivo knockdown of ICAM5 in the dentate gyrus rescued the impaired spatial and fear memory and anxiety-like behaviors in Fmr1 KO mice, through both granule cell and mossy cell with a relative rate of 1.32 ± 0.15. Furthermore, biochemical analyses showed direct binding of FMRP with ICAM5 mRNA, to the coding sequence of ICAM5 mRNA. Together, our study suggests that ICAM5 is one of the targets of FMRP and is implicated in the molecular pathogenesis of FXS. ICAM5 could be a therapeutic target for treating cognitive impairment in FXS. SIGNIFICANCE STATEMENT Fragile X syndrome (FXS) is characterized by dendritic spine dysgenesis and cognitive dysfunctions, while one of the FMRP latent targets, ICAM5, is well established for contributing both spine maturation and learning performance. In this study, we examined the potential link between ICAM5 mRNA and FMRP in FXS, and further investigated the molecular details and pathological consequences of ICAM5 overexpression. Our results indicate a critical role of ICAM5 in spine maturation and cognitive impairment in FXS and suggest that ICAM5 is a potential molecular target for the development of medication against FXS.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2626-18.2019
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    Fast high-resolution metabolic imaging of acute stroke with 3D magnetic resonance spectroscopy
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 11 ( 2020-11-01), p. 3225-3233
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 11 ( 2020-11-01), p. 3225-3233
    Abstract: Impaired oxygen and cellular metabolism is a hallmark of ischaemic injury in acute stroke. Magnetic resonance spectroscopic imaging (MRSI) has long been recognized as a potentially powerful tool for non-invasive metabolic imaging. Nonetheless, long acquisition time, poor spatial resolution, and narrow coverage have limited its clinical application. Here we investigated the feasibility and potential clinical utility of rapid, high spatial resolution, near whole-brain 3D metabolic imaging based on a novel MRSI technology. In an 8-min scan, we simultaneously obtained 3D maps of N-acetylaspartate and lactate at a nominal spatial resolution of 2.0 × 3.0 × 3.0 mm3 with near whole-brain coverage from a cohort of 18 patients with acute ischaemic stroke. Serial structural and perfusion MRI was used to define detailed spatial maps of tissue-level outcomes against which high-resolution metabolic changes were evaluated. Within hypoperfused tissue, the lactate signal was higher in areas that ultimately infarcted compared with those that recovered (P  & lt; 0.0001). Both lactate (P  & lt; 0.0001) and N-acetylaspartate (P  & lt; 0.001) differed between infarcted and other regions. Within the areas of diffusion-weighted abnormality, lactate was lower where recovery was observed compared with elsewhere (P  & lt; 0.001). This feasibility study supports further investigation of fast high-resolution MRSI in acute stroke.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa264
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Frequent pattern discovery with tri-partition alphabets
    Elsevier BV ; 2020
    In:  Information Sciences Vol. 507 ( 2020-01), p. 715-732
    Details
    In: Information Sciences, Elsevier BV, Vol. 507 ( 2020-01), p. 715-732
    Type of Medium: Online Resource
    ISSN: 0020-0255
    URL: Article
    DOI: 10.1016/j.ins.2018.04.013
    RVK:
    SA 5420
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    SSG: 24,1
    SSG: 7,11
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  • 5
    Online Resource
    Online Resource
    PSAP intronic variants around saposin D domain and Parkinson’s disease
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 1 ( 2021-02-12), p. e3-e3
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 1 ( 2021-02-12), p. e3-e3
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa354
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 48 ( 2021-11-30)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 48 ( 2021-11-30)
    Abstract: Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2115158118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 7
    Online Resource
    Online Resource
    Quantum walks on a programmable two-dimensional 62-qubit superconducting processor
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Vol. 372, No. 6545 ( 2021-05-28), p. 948-952
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 372, No. 6545 ( 2021-05-28), p. 948-952
    Abstract: Quantum walks are the quantum mechanical analog of classical random walks and an extremely powerful tool in quantum simulations, quantum search algorithms, and even for universal quantum computing. In our work, we have designed and fabricated an 8-by-8 two-dimensional square superconducting qubit array composed of 62 functional qubits. We used this device to demonstrate high-fidelity single- and two-particle quantum walks. Furthermore, with the high programmability of the quantum processor, we implemented a Mach-Zehnder interferometer where the quantum walker coherently traverses in two paths before interfering and exiting. By tuning the disorders on the evolution paths, we observed interference fringes with single and double walkers. Our work is a milestone in the field, bringing future larger-scale quantum applications closer to realization for noisy intermediate-scale quantum processors.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg7812
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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    SSG: 11
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  • 8
    Online Resource
    Online Resource
    AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood–Brain Barrier
    Society for Neuroscience ; 2022
    In:  The Journal of Neuroscience Vol. 42, No. 43 ( 2022-10-26), p. 8169-8183
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 42, No. 43 ( 2022-10-26), p. 8169-8183
    Abstract: Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4 A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4 A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood–brain barrier. The infarct volume and neuronal damage were also reduced in AQP4 A25Q/A25Q mice in the middle cerebral artery occlusion/reperfusion model. Astrocyte activation in the brain was alleviated in AQP4 A25Q/A25Q mice, which may be associated with decreased cell swelling. We conclude that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood–brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation. SIGNIFICANCE STATEMENT Aquaporin-4 (AQP4) is characterized by orthogonal arrays of particles (OAPs) comprising the M1 and M23 isoforms in the membrane. Here, an OAP depolymerization male mouse model induced by AQP4-A25Q mutation was first established, and the functions of OAP depolymerization in cerebral edema have been studied. The results revealed that AQP4 lost its OAP structure without affecting AQP4 mRNA and protein levels in AQP4-A25Q mice. AQP4-A25Q mutation mice has neuroprotective effects on cerebral edema induced by water intoxication and middle cerebral artery occlusion/reperfusion through relieving the activation of astrocytes and suppressed microglia-mediated neuroinflammation. We concluded that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood–brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.0401-22.2022
    DOI: 10.1523/JNEUROSCI.0401-22.2022.tab1-1
    DOI: 10.1523/JNEUROSCI.0401-22.2022.tab2-1
    DOI: 10.1523/JNEUROSCI.0401-22.2022.f7-2
    DOI: 10.1523/JNEUROSCI.0401-22.2022.f7-1
    DOI: 10.1523/JNEUROSCI.0401-22.2022.f6-1
    DOI: 10.1523/JNEUROSCI.0401-22.2022.f5-2
    DOI: 10.1523/JNEUROSCI.0401-22.2022.f5-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2022
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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