IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60294-3.html
   My bibliography  Save this article

Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis

Author

Listed:
  • Manu Ahmed

    (University of Massachusetts Chan Medical School)

  • Sydney Fischer

    (University of Massachusetts Chan Medical School)

  • Karyn L. Robert

    (University of Massachusetts Chan Medical School)

  • Karen I. Lange

    (University College Dublin)

  • Michael W. Stuck

    (University of Massachusetts Chan Medical School)

  • Sunayna Best

    (The University of Leeds
    Leeds Teaching Hospitals NHS Trust)

  • Colin A. Johnson

    (The University of Leeds)

  • Gregory J. Pazour

    (University of Massachusetts Chan Medical School)

  • Oliver E. Blacque

    (University College Dublin)

  • Sumeda Nandadasa

    (University of Massachusetts Chan Medical School)

Abstract

TMEM67 mutations cause Meckel-Gruber syndrome and other related ciliopathies. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: a C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67-/- mice, but in contrast, transduces normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.

Suggested Citation

  • Manu Ahmed & Sydney Fischer & Karyn L. Robert & Karen I. Lange & Michael W. Stuck & Sunayna Best & Colin A. Johnson & Gregory J. Pazour & Oliver E. Blacque & Sumeda Nandadasa, 2025. "Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60294-3
    DOI: 10.1038/s41467-025-60294-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60294-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60294-3?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
    ---><---

    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:16:y:2025:i:1:d:10.1038_s41467-025-60294-3. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.