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  • 1
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    DOCK2 is involved in the host genetics and biology of severe COVID-19
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene ( DOCK2 ), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis ( n  = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05163-5
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Identification of ARIA regulating endothelial apoptosis and angiogenesis by modulating proteasomal degradation of cIAP-1 and cIAP-2
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 20 ( 2009-05-19), p. 8227-8232
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 20 ( 2009-05-19), p. 8227-8232
    Abstract: Endothelial apoptosis is a pivotal process for angiogenesis during embryogenesis as well as postnatal life. By using a retrovirus-mediated signal sequence trap method, we identified a previously undescribed gene, termed ARIA (apoptosis regulator through modulating IAP expression), which regulates endothelial apoptosis and angiogenesis. ARIA was expressed in blood vessels during mouse embryogenesis, as well as in endothelial cells both in vitro and in vivo. ARIA is a unique protein with no homology to previously reported conserved domain structures. Knockdown of ARIA in HUVECs by using small interfering RNA significantly reduced endothelial apoptosis without affecting either cell migration or proliferation. ARIA knockdown significantly increased inhibitor of apoptosis (cIAP)-1 and cIAP-2 protein expression, although their mRNA expression was not changed. Simultaneous knockdown of cIAP-1 and cIAP-2 abolished the antiapoptotic effect of ARIA knockdown. Using yeast 2-hybrid screening, we identified the interaction of ARIA with 20S proteasome subunit α-7. Thereafter, we found that cIAP-1 and cIAP-2 were degraded by proteasomes in endothelial cells under normal condition. Overexpression of ARIA significantly reduced cIAP-1 expression, and this reduction was abolished by proteasomal inhibition in BAECs. Also, knockdown of ARIA demonstrated an effect similar to proteasomal inhibition with respect to not only expression but also subcellular localization of cIAP-1 and cIAP-2. In vivo angiogenesis studied by Matrigel-plug assay, mouse ischemic retinopathy model, and tumor xenograft model was significantly enhanced by ARIA knockdown. Together, our data indicate that ARIA is a unique factor regulating endothelial apoptosis, as well as angiogenesis, presumably through modulating proteasomal degradation of cIAP-1 and cIAP-2 in endothelial cells.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0806780106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
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  • 3
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    Autoreactive T Cell Response in CD25‐Negative Fraction of Peripheral Blood Mononuclear Cells in Established Type 1 Diabetes
    Wiley ; 2008
    In:  Annals of the New York Academy of Sciences Vol. 1150, No. 1 ( 2008-12), p. 278-281
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1150, No. 1 ( 2008-12), p. 278-281
    Abstract: CD4 + CD25 + T cells (Tregs) play a critical role in maintaining dominant peripheral tolerance, and pathogenic autoreactive T cells may be frequent in the CD25‐negative fraction of peripheral blood mononuclear cells (PBMCs) from patients with autoimmune disease. We therefore investigated whether T cell autoimmune responses to recombinant GAD65 can be detected by the use of ELISPOT assay in the CD25‐negative fraction of PMBCs from Japanese type 1 diabetes (T1D) patients. The frequency of CD4 + CD25 + T cells was not different among patients with newly developed T1D, established T1D, and healthy controls. The CD25 positive cell–depleted fraction was obtained by negative selection with antihuman CD25 magnetic beads, reducing the number of CD4 + CD25 + T cells from 4–5% to less than 1%. In whole PBMC fraction, there was a significant elevation of IFN‐γ spots in PBMCs from recently diagnosed patients with T1D ( P 〈 0.05), whereas the number of IFN‐γ spots from patients with established T1D was not significant. In the CD25‐negative fraction, unlike whole PBMCs, we observed the significant IFN‐γ spots to GAD65 in the fraction from patients with established T1D ( P 〈 0.05), but not in those with recently diagnosed disease. The phenomena were not observed for IL‐4 spots. Our data suggest a possible role of Tregs maintaining dominant peripheral tolerance in T1D and application of further improved T cell assay detecting autoimmunity even in established T1D.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1196/nyas.2008.1150.issue-1
    DOI: 10.1196/annals.1447.007
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
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  • 4
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    Apoptosis regulator through modulating IAP expression (ARIA) controls the PI3K/Akt pathway in endothelial and endothelial progenitor cells
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 23 ( 2011-06-07), p. 9472-9477
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 23 ( 2011-06-07), p. 9472-9477
    Abstract: Endothelial and endothelial progenitor cells (ECs and EPCs) play a fundamental role in angiogenesis that is essential for numerous physiological and pathological processes. The phosphatase and tensin homolog (PTEN)/ phosphoinositide 3-kinase (PI3K) pathway has been implicated in angiogenesis, but the mechanism in the regulation of this pathway in ECs and EPCs is poorly understood. Here we show that ARIA (apoptosis regulator through modulating IAP expression), a transmembrane protein that we recently identified, regulates the PTEN/PI3K pathway in ECs and EPCs and controls developmental and postnatal angiogenesis in vivo. We found that ARIA is abundantly expressed in EPCs and regulates their angiogenic functions by modulating PI3K/Akt/endothelial nitric oxide synthase (eNOS) signaling. Genetic deletion of ARIA caused nonfatal bleeding during embryogenesis, in association with increased small vessel density and altered expression of various vascular growth factors including angiopoietins and VEGF receptors. Postnatal neovascularization induced by critical limb ischemia was substantially enhanced in ARIA-null mice, in conjunction with more bone marrow (BM)-derived ECs detected in ischemic muscles. Administration of PI3K or NO synthase inhibitor completely abolished the enhanced neovascularization in ARIA −/− mice. Mechanistically, we identified that ARIA interacts with PTEN at the intracellular domain independently of the PTEN phosphorylation in its C-terminal tail. Overexpressed ARIA increased PTEN in the membrane fraction, whereas ARIA-silencing reduced the membrane-associated PTEN, resulting in modified PI3K/Akt signaling. Taken together, our findings establish a previously undescribed mode of regulation of the PTEN/PI3K/Akt pathway by ARIA, and reveal a unique mechanism in the control of angiogenesis. These functions of ARIA might offer a unique therapeutic potential.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1101296108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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  • 5
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    Carbohydrate-binding domain of the POMGnT1 stem region modulates O -mannosylation sites of α-dystroglycan
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 33 ( 2016-08-16), p. 9280-9285
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 33 ( 2016-08-16), p. 9280-9285
    Abstract: The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O -mannose–type GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O -mannosyl glycan synthesis. Defects in protein O -linked mannose β1,2- N -acetylglucosaminyltransferase 1 (POMGnT1), a glycosyltransferase that participates in the formation of GlcNAc-β1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGnT1 in postphosphoryl modification of GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGnT1 agreed with our previous results showing that the catalytic domain recognizes substrate O -mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the stem domain recognizes the β-linked GlcNAc of O -mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of α-DG to promote GlcNAc-β1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGnT1 -KO mice and MEB patients.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1525545113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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  • 6
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    Characterization of H7N9 influenza A viruses isolated from humans
    Springer Science and Business Media LLC ; 2013
    In:  Nature Vol. 501, No. 7468 ( 2013-9), p. 551-555
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 501, No. 7468 ( 2013-9), p. 551-555
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature12392
    RVK:
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    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
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  • 7
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    Crystal structures of two tropinone reductases: Different reaction stereospecificities in the same protein fold
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 9 ( 1998-04-28), p. 4876-4881
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 9 ( 1998-04-28), p. 4876-4881
    Abstract: A pair of tropinone reductases (TRs) share 64% of the same amino acid residues and belong to the short-chain dehydrogenase/reductase family. In the synthesis of tropane alkaloids in several medicinal plants, the TRs reduce a carbonyl group of an alkaloid intermediate, tropinone, to hydroxy groups with different diastereomeric configurations. To clarify the structural basis for their different reaction stereospecificities, we determined the crystal structures of the two enzymes at 2.4- and 2.3-Å resolutions. The overall folding of the two enzymes was almost identical. The conservation was not confined within the core domains that are conserved within the protein family but extended outside the core domain where each family member has its characteristic structure. The binding sites for the cofactor and the positions of the active site residues were well conserved between the two TRs. The substrate binding site was composed mostly of hydrophobic amino acids in both TRs, but the presence of different charged residues conferred different electrostatic environments on the two enzymes. A modeling study indicated that these charged residues play a major role in controlling the binding orientation of tropinone within the substrate binding site, thereby determining the stereospecificity of the reaction product. The results obtained herein raise the possibility that in certain cases different stereospecificities can be acquired in enzymes by changing a few amino acid residues within substrate binding sites.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.9.4876
    RVK:
    TA 1000
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    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
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  • 8
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    Intravenous Administration of Proinsulin 1 or 2–Expressing Fiber‐Mutant Recombinant Adenovirus Vector Protects against the Development of Diabetes in NOD Mice
    Wiley ; 2008
    In:  Annals of the New York Academy of Sciences Vol. 1150, No. 1 ( 2008-12), p. 183-186
    Details
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1150, No. 1 ( 2008-12), p. 183-186
    Abstract: Insulin has been reported as a major autoantigen in both human and murine type 1 diabetes (T1D). Insulin1‐knockout NOD mice with only insulin2 are protected against the development of autoimmune diabetes, suggesting that insulin1 has strong immunogenicity and insulin2 has weak immunogenicity or a possible protective role in the pathogenesis of type 1 diabetes. In this study, we have developed fiber‐mutant adenovirus vectors that express murine proinsulin1 or proinsulin2 (named Ad.Pins1‐RGD/Ad.Pins2‐RGD) and administered those virus vectors to the NOD mouse to evaluate modulation of autoimmune responses. The intravenous administration of either Ad.Pins1‐RGD or Ad.Pins2‐RGD at 3 and 5 weeks of age strongly suppressed the development of overt diabetes, accompanied by a significant reduction of insulin autoantibody (IAA), and suppression of disease was similar between administration of Ad.Pins1‐RGD and that of Ad.Pins2‐RGD. Our study suggests that systemic administration of fiber‐mutant adenovirus vectors, which induce transient expression of proinsulin, may be applicable to a gene therapy inducing tolerance to insulin.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
    URL: Issue
    URL: Article
    DOI: 10.1196/nyas.2008.1150.issue-1
    DOI: 10.1196/annals.1447.006
    RVK:
    TD 7650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2834079-6
    detail.hit.zdb_id: 211003-9
    detail.hit.zdb_id: 2071584-5
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  • 9
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    Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 28 ( 2020-07-14), p. 16587-16595
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 28 ( 2020-07-14), p. 16587-16595
    Abstract: At the end of 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) was detected in Wuhan, China, that spread rapidly around the world, with severe consequences for human health and the global economy. Here, we assessed the replicative ability and pathogenesis of SARS-CoV-2 isolates in Syrian hamsters. SARS-CoV-2 isolates replicated efficiently in the lungs of hamsters, causing severe pathological lung lesions following intranasal infection. In addition, microcomputed tomographic imaging revealed severe lung injury that shared characteristics with SARS-CoV-2−infected human lung, including severe, bilateral, peripherally distributed, multilobular ground glass opacity, and regions of lung consolidation. SARS-CoV-2−infected hamsters mounted neutralizing antibody responses and were protected against subsequent rechallenge with SARS-CoV-2. Moreover, passive transfer of convalescent serum to naïve hamsters efficiently suppressed the replication of the virus in the lungs even when the serum was administrated 2 d postinfection of the serum-treated hamsters. Collectively, these findings demonstrate that this Syrian hamster model will be useful for understanding SARS-CoV-2 pathogenesis and testing vaccines and antiviral drugs.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2009799117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
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  • 10
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    Pressure-dissociable reversible assembly of intrinsically denatured lysozyme is a precursor for amyloid fibrils
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 12 ( 2004-03-23), p. 4089-4093
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 12 ( 2004-03-23), p. 4089-4093
    Abstract: Although a diversity of proteins is known to form amyloid fibers, their common mechanisms are not clear. Here, we show that an intrinsically unfolded protein (U), represented by a disulfide-deficient variant of hen lysozyme with no tertiary structure, forms an amyloid-like fibril after prolonged incubation. Using variable pressure NMR along with sedimentation velocity, circular dichroism, and fluorescence measurements, we show that, before the fibril formation, the protein forms a pressure-dissociable, soluble assemblage ( \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{U}}_{{\mathrm{n}}}^{^{\prime}}\end{equation*}\end{document} ) with a sedimentation coefficient of 17 S and a rich intermolecular β-sheet structure. The reversible assemblage is characterized with a Gibbs energy for association of –23.3 ± 0.8 kJ·mol –1 and a volume increase of 52.7 ± 11.3 ml·mol –1 per monomer unit, and involves preferential interaction of hydrophobic residues in the initial association step. These results indicate that amyloid fibril formation can proceed from an intrinsically denatured protein and suggest a scheme \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{N}}{\Leftrightarrow}{\mathrm{U}}{\Leftrightarrow}{\mathrm{U}}_{{\mathrm{n}}}^{^{\prime}}{\rightarrow}{\mathrm{fibril}}\end{equation*}\end{document} as a common mechanism of fibril formation in amyloidogenic proteins, where two-way arrows represent reversible processes, one-way arrow represents an irreversible process, and N, U, and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{U}}_{{\mathrm{n}}}^{^{\prime}}\end{equation*}\end{document} represent, respectively, the native conformer, the unfolded monomeric conformer, and the soluble assemblage of unfolded conformers.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0305798101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
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    SSG: 11
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