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Identification of global inhibitors of cellular glycosylation

Author

Listed:
  • Daniel Madriz Sørensen

    (University of Copenhagen)

  • Christian Büll

    (University of Copenhagen
    Radboud University)

  • Thomas D. Madsen

    (University of Copenhagen
    Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Erandi Lira-Navarrete

    (University of Copenhagen
    The Institute for Biocomputation and Physics of Complex Systems (BIFI), Mariano Esquillor s/n, Campus Rio Ebro
    Fundación ARAID)

  • Thomas Mandel Clausen

    (University of Copenhagen
    University of Hawaii
    University of California, San Diego)

  • Alex E. Clark

    (Department of Medicine, University of California, San Diego)

  • Aaron F. Garretson

    (Department of Medicine, University of California, San Diego)

  • Richard Karlsson

    (University of Copenhagen)

  • Johan F. A. Pijnenborg

    (Radboud University Nijmegen)

  • Xin Yin

    (Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road)

  • Rebecca L. Miller

    (University of Copenhagen)

  • Sumit K. Chanda

    (Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road)

  • Thomas J. Boltje

    (Radboud University Nijmegen)

  • Katrine T. Schjoldager

    (University of Copenhagen)

  • Sergey Y. Vakhrushev

    (University of Copenhagen)

  • Adnan Halim

    (University of Copenhagen)

  • Jeffrey D. Esko

    (University of California, San Diego)

  • Aaron F. Carlin

    (University of California, San Diego)

  • Ramon Hurtado-Guerrero

    (University of Copenhagen
    The Institute for Biocomputation and Physics of Complex Systems (BIFI), Mariano Esquillor s/n, Campus Rio Ebro
    Fundación ARAID)

  • Roberto Weigert

    (Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Henrik Clausen

    (University of Copenhagen)

  • Yoshiki Narimatsu

    (University of Copenhagen
    GlycoDisplay ApS)

Abstract

Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.

Suggested Citation

  • Daniel Madriz Sørensen & Christian Büll & Thomas D. Madsen & Erandi Lira-Navarrete & Thomas Mandel Clausen & Alex E. Clark & Aaron F. Garretson & Richard Karlsson & Johan F. A. Pijnenborg & Xin Yin & , 2023. "Identification of global inhibitors of cellular glycosylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36598-7
    DOI: 10.1038/s41467-023-36598-7
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    References listed on IDEAS

    as
    1. Weihua Tian & Zilu Ye & Shengjun Wang & Morten Alder Schulz & Julie Coillie & Lingbo Sun & Yen-Hsi Chen & Yoshiki Narimatsu & Lars Hansen & Claus Kristensen & Ulla Mandel & Eric Paul Bennett & Siamak , 2019. "The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Yi Xiang & Xiaoyan Zhang & David B Nix & Toshihiko Katoh & Kazuhiro Aoki & Michael Tiemeyer & Yanzhuang Wang, 2013. "Erratum: Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65," Nature Communications, Nature, vol. 4(1), pages 1-2, October.
    3. Marko T. Boskovski & Shiaulou Yuan & Nis Borbye Pedersen & Christoffer Knak Goth & Svetlana Makova & Henrik Clausen & Martina Brueckner & Mustafa K. Khokha, 2013. "The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality," Nature, Nature, vol. 504(7480), pages 456-459, December.
    4. Yi Xiang & Xiaoyan Zhang & David B. Nix & Toshihiko Katoh & Kazuhiro Aoki & Michael Tiemeyer & Yanzhuang Wang, 2013. "Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65," Nature Communications, Nature, vol. 4(1), pages 1-14, June.
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    Cited by:

    1. Pranav Kumar & Tadakimi Tomita & Thomas A. Gerken & Collin J. Ballard & Yong Sok Lee & Louis M. Weiss & Nadine L. Samara, 2024. "A Toxoplasma gondii O-glycosyltransferase that modulates bradyzoite cyst wall rigidity is distinct from host homologues," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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