IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42227-0.html
   My bibliography  Save this article

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

Author

Listed:
  • Duc T. Huynh

    (Duke University School of Medicine)

  • Kalina N. Tsolova

    (Duke University School of Medicine)

  • Abigail J. Watson

    (Duke University School of Medicine)

  • Sai Kwan Khal

    (Duke University School of Medicine)

  • Jordan R. Green

    (Duke University School of Medicine)

  • Di Li

    (Duke University School of Medicine)

  • Jimin Hu

    (Duke University School of Medicine)

  • Erik J. Soderblom

    (Duke University School of Medicine)

  • Jen-Tsan Chi

    (Duke University School of Medicine)

  • Chantell S. Evans

    (Duke University School of Medicine)

  • Michael Boyce

    (Duke University School of Medicine
    Duke University School of Medicine)

Abstract

The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.

Suggested Citation

  • Duc T. Huynh & Kalina N. Tsolova & Abigail J. Watson & Sai Kwan Khal & Jordan R. Green & Di Li & Jimin Hu & Erik J. Soderblom & Jen-Tsan Chi & Chantell S. Evans & Michael Boyce, 2023. "O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42227-0
    DOI: 10.1038/s41467-023-42227-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42227-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-42227-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Michael B. Lazarus & Yunsun Nam & Jiaoyang Jiang & Piotr Sliz & Suzanne Walker, 2011. "Structure of human O-GlcNAc transferase and its complex with a peptide substrate," Nature, Nature, vol. 469(7331), pages 564-567, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ping Lu & Yusong Liu & Maozhou He & Ting Cao & Mengquan Yang & Shutao Qi & Hongtao Yu & Haishan Gao, 2023. "Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Richard W. Meek & James N. Blaza & Jil A. Busmann & Matthew G. Alteen & David J. Vocadlo & Gideon J. Davies, 2021. "Cryo-EM structure provides insights into the dimer arrangement of the O-linked β-N-acetylglucosamine transferase OGT," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Shivesh Kumar & Yan Wang & Ye Zhou & Lucas Dillard & Fay-Wei Li & Carly A. Sciandra & Ning Sui & Rodolfo Zentella & Emily Zahn & Jeffrey Shabanowitz & Donald F. Hunt & Mario J. Borgnia & Alberto Barte, 2023. "Structure and dynamics of the Arabidopsis O-fucosyltransferase SPINDLY," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Shiyang Cao & Tong Wang & Yifan Ren & Gengshan Wu & Yuan Zhang & Yafang Tan & Yazhou Zhou & Hongyan Chen & Yu Zhang & Yajun Song & Ruifu Yang & Zongmin Du, 2024. "A protein O-GlcNAc glycosyltransferase regulates the antioxidative response in Yersinia pestis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42227-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.