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  • 1
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    Online Resource
    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
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-08-06)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-08-06)
    Abstract: Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient’s CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-70203-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 3
    Online Resource
    Online Resource
    NF-κB Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells
    American Society for Microbiology ; 2011
    In:  Journal of Virology Vol. 85, No. 7 ( 2011-04), p. 3179-3186
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 85, No. 7 ( 2011-04), p. 3179-3186
    Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-κB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-α), which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-α and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-κB activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-κB binding sites (designated κB-1 and κB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-κB component p65/RelA. Mutation of the κB-1 site, but not the κB-2 site, impaired responsiveness to TNF-α and LMP1 in reporter assays. A mutant XMRV with a mutation at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-α and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the κB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-κB activation may promote XMRV spread in humans.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02333-10
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2011
    detail.hit.zdb_id: 1495529-5
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  • 4
    Online Resource
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    Single-cell analyses and host genetics highlight the role of innate immune cells in COVID-19 severity
    Springer Science and Business Media LLC ; 2023
    In:  Nature Genetics Vol. 55, No. 5 ( 2023-05), p. 753-767
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 55, No. 5 ( 2023-05), p. 753-767
    Abstract: Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of 〉 895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/s41588-023-01375-1
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 5
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    Opposing roles of RUBCN isoforms in autophagy and memory B cell generation
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Signaling Vol. 16, No. 803 ( 2023-09-19)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 16, No. 803 ( 2023-09-19)
    Abstract: Memory B cells generated upon the first encounter with a pathogen persist to enable antibody-based defenses for subsequent encounters. The survival of memory B cells depends on autophagy, a process that eliminates damaged cellular components. The 130–amino acid protein Rubicon (RUBCN 130 ) is thought to inhibit autophagy, and Tsai et al . characterized a shorter Rubicon isoform (RUBCN 100 ) that enhanced autophagy in B cells. Mice with B cells that specifically lacked RUBCN 130 generated more memory B cells in an autophagy-dependent manner. The differential effects on autophagy might be due to the ability of RUBCN 130 to suppress the activity of autophagy-promoting proteins. The identification and characterization of the shorter Rubicon isoform help to resolve conflicting results regarding the function of Rubicon in autophagy. —Wei Wong
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.ade3599
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 6
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    Accumulation of Heterochromatin Components on the Terminal Repeat Sequence of Kaposi's Sarcoma-Associated Herpesvirus Mediated by the Latency-Associated Nuclear Antigen
    American Society for Microbiology ; 2004
    In:  Journal of Virology Vol. 78, No. 14 ( 2004-07-15), p. 7299-7310
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 78, No. 14 ( 2004-07-15), p. 7299-7310
    Abstract: In the latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), its 160-kb circularized episomal DNA is replicated and maintained in the host nucleus. KSHV latency-associated nuclear antigen (LANA) is a key factor for maintaining viral latency. LANA binds to the terminal repeat (TR) DNA of the viral genome, leading to its localization to specific dot structures in the nucleus. In such an infected cell, the expression of the viral genes is restricted by a mechanism that is still unclear. Here, we found that LANA interacts with SUV39H1 histone methyltransferase, a key component of heterochromatin formation, as determined by use of a DNA pull-down assay with a biotinylated DNA fragment that contained a LANA-specific binding sequence and a maltose-binding protein pull-down assay. The diffuse localization of LANA on the chromosomes of uninfected cells changed to a punctate one with the introduction of a bacterial artificial chromosome containing most of the TR region, and SUV39H1 clearly colocalized with the LANA-associated dots. Thus, the LANA foci in KSHV-infected cells seemed to include SUV39H1 as well as heterochromatin protein 1. Furthermore, a chromatin immunoprecipitation assay revealed that the TR and the open reading frame (ORF) K1 and ORF50/RTA genes, but not the ORF73/LANA gene, lay within the heterochromatin during KSHV latency. Taken together, these observations indicate that LANA recruits heterochromatin components to the viral genome, which may lead to the establishment of viral latency and govern the transcription program.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.78.14.7299-7310.2004
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2004
    detail.hit.zdb_id: 1495529-5
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  • 7
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    Epstein-Barr Virus Nuclear Protein 3C Domains Necessary for Lymphoblastoid Cell Growth: Interaction with RBP-Jκ Regulates TCL1
    American Society for Microbiology ; 2009
    In:  Journal of Virology Vol. 83, No. 23 ( 2009-12), p. 12368-12377
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 83, No. 23 ( 2009-12), p. 12368-12377
    Abstract: B lymphocytes converted into lymphoblastoid cell lines (LCLs) by an Epstein-Barr virus that expresses a conditional EBNA3C require complementation with EBNA3C for growth under nonpermissive conditions. Complementation with relatively large EBNA3C deletion mutants identified amino acids (aa) 1 to 506 (which includes the RBP-Jκ/CSL [RBP-Jκ] binding domain) and 733 to 909 to be essential for LCL growth, aa 728 to 732 and 910 to 992 to be important for full wild-type (wt) growth, and only aa 507 to 727 to be unimportant (S. Maruo, Y. Wu, T. Ito, T. Kanda, E. D. Kieff, and K. Takada, Proc. Natl. Acad. Sci. USA 106: 4419-4424, 2009). When mutants with smaller deletions were used, only aa 51 to 400 and 851 to 900 were essential for LCL growth; aa 447 to 544, 701 to 750, 801 to 850, and 901 to 992 were important for full wt growth; and aa 4 to 50, 401 to 450, 550 to 707, and 751 to 800 were unimportant. These data reduce the EBNA3C essential residues from 68% to 40% of the open reading frame. Point mutations confirmed RBP-Jκ binding to be essential for wt growth and indicated that SUMO and CtBP binding interactions were important only for full wt growth. EBNA3C aa 51 to 150, 249 to 311, and 851 to 900 were necessary for maintaining LCL growth, but not RBP-Jκ interaction, and likely mediate interactions with other key cell proteins. Moreover, all mutants null for LCL growth had fewer S+G 2 /M-phase cells at 14 days, consistent with EBNA3C interaction with RBP-Jκ as well as aa 51 to 150, 249 to 311, and 851 to 900 being required to suppress p16 INK4A (S. Maruo, Y. Wu, S. Ishikawa, T. Kanda, D. Iwakiri, and K. Takada, Proc. Natl. Acad. Sci. USA 103: 19500-19505, 2006). We have confirmed that EBNA3C upregulates TCL1 and discovered that EBNA3C upregulates TCL1 through RBP-Jκ, indicating a central role for EBNA3C interaction with RBP-Jκ in mediating cell gene transcription.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01403-09
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
    detail.hit.zdb_id: 1495529-5
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  • 8
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    Gene Regulation and Functional Alterations Induced by Kaposi's Sarcoma-Associated Herpesvirus-Encoded ORFK13/vFLIP in Endothelial Cells
    American Society for Microbiology ; 2009
    In:  Journal of Virology Vol. 83, No. 5 ( 2009-03), p. 2140-2153
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 83, No. 5 ( 2009-03), p. 2140-2153
    Abstract: Kaposi's sarcoma (KS) is an angioproliferative inflammatory disorder induced by endothelial cell infection with the KS-associated herpesvirus (KSHV). ORFK13/vFLIP , one of the KSHV genes expressed in KS, encodes a 188-amino-acid protein which binds to the Iκb kinase (IKK) complex to activate NF-κB. We examined ORFK13/vFLIP contribution to KS phenotype and potential for therapeutic targeting. Retroviral transduction of ORFK13/vFLIP into primary human endothelial cells induces the spindle morphology distinctive of KS cells and promotes the formation of abnormal vascular networks typical of KS vasculature; upregulates the expression of proinflammatory cytokines, chemokines, and interferon-responsive genes; and stimulates the adhesion of inflammatory cells characteristic of KS lesions. Thymidine phosphorylase, a cellular enzyme markedly induced by ORFK13/vFLIP , can metabolize the prodrug 5-fluoro-5-deoxyuridine (5-dFUrd) to 5-fluouridine (5-FU), a potent thymidine synthase inhibitor, which blocks DNA and RNA synthesis. When tested for cytotoxicity, 5-dFUrd (0.1 to 1 μM) selectively killed ORFK13/vFLIP -expressing endothelial cells while sparing control cells. These results demonstrate that ORFK13/vFLIP directly and indirectly contributes to the inflammatory and vascular phenotype of KS and identify 5-dFUrd as a potential new drug that targets KSHV latency for the treatment of KS and other KSHV-associated malignancies.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01871-08
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
    detail.hit.zdb_id: 1495529-5
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  • 9
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    Transcriptomic, Hormonomic and Metabolomic Analyses Highlighted the Common Modules Related to Photosynthesis, Sugar Metabolism and Cell Division in Parthenocarpic Tomato Fruits during Early Fruit Set
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 9 ( 2022-04-22), p. 1420-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 9 ( 2022-04-22), p. 1420-
    Abstract: Parthenocarpy, the pollination-independent fruit set, can raise the productivity of the fruit set even under adverse factors during the reproductive phase. The application of plant hormones stimulates parthenocarpy, but artificial hormones incur extra financial and labour costs to farmers and can induce the formation of deformed fruit. This study examines the performance of parthenocarpic mutants having no transcription factors of SlIAA9 and SlTAP3 and sldella that do not have the protein-coding gene, SlDELLA, in tomato (cv. Micro-Tom). At 0 day after the flowering (DAF) stage and DAFs after pollination, the sliaa9 mutant demonstrated increased pistil development compared to the other two mutants and wild type (WT). In contrast to WT and the other mutants, the sliaa9 mutant with pollination efficiently stimulated the build-up of auxin and GAs after flowering. Alterations in both transcript and metabolite profiles existed for WT with and without pollination, while the three mutants without pollination demonstrated the comparable metabolomic status of pollinated WT. Network analysis showed key modules linked to photosynthesis, sugar metabolism and cell proliferation. Equivalent modules were noticed in the famous parthenocarpic cultivars ‘Severianin’, particularly for emasculated samples. Our discovery indicates that controlling the genes and metabolites proffers future breeding policies for tomatoes.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11091420
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 10
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    The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1
    American Society of Hematology ; 2010
    In:  Blood Vol. 115, No. 19 ( 2010-05-13), p. 3970-3979
    Details
    In: Blood, American Society of Hematology, Vol. 115, No. 19 ( 2010-05-13), p. 3970-3979
    Abstract: The transcription factor growth factor independence 1 (Gfi1) and the growth factor granulocyte colony-stimulating factor (G-CSF) are individually essential for neutrophil differentiation from myeloid progenitors. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of Ras guanine nucleotide releasing protein 1 (RasGRP1), an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/mitogen–activated protein/extracellular signal-regulated kinase (MEK/Erk) pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not signal transducer and activator of transcription 1 (STAT1) or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknown function of Gfi1 as a regulator of RasGRP1 and link Gfi1 transcriptional control to G-CSF signaling and regulation of granulopoiesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2009-10-246967
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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