1. Cell Biology

Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin

  1. Melissa V Gammons
  2. Miha Renko
  3. Joshua E Flack
  4. Juliusz Mieszczanek
  5. Mariann Bienz  Is a corresponding author
  1. Medical Research Council, United Kingdom
https://doi.org/10.7554/eLife.59879
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  1. Melissa V Gammons
  2. Miha Renko
  3. Joshua E Flack
  4. Juliusz Mieszczanek
  5. Mariann Bienz
(2020)
Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin
eLife 9:e59879.
https://doi.org/10.7554/eLife.59879
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Abstract

Feedback control is a universal feature of cell signaling pathways. Naked/NKD is a widely conserved feedback regulator of Wnt signaling which controls animal development and tissue homeostasis. Naked/NKD destabilizes Dishevelled, which assembles Wnt signalosomes to inhibit the b-catenin destruction complex via recruitment of Axin. Here, we discover that the molecular mechanism underlying Naked/NKD function relies on its assembly into ultrastable decameric core aggregates via its conserved C-terminal histidine cluster (HisC). HisC aggregation is facilitated by Dishevelled and depends on accumulation of Naked/NKD during prolonged Wnt stimulation. Naked/NKD HisC cores co-aggregate with a conserved histidine cluster within Axin, to destabilize it along with Dishevelled, possibly via the autophagy receptor p62 which binds to HisC aggregates. Consistent with this, attenuated Wnt responses are observed in CRISPR-engineered flies and human epithelial cells whose Naked/NKD HisC has been deleted. Thus, HisC aggregation by Naked/NKD provides context-dependent feedback control of prolonged Wnt responses.

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All data generated and analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Melissa V Gammons

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9661-9331

  2. Miha Renko

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Joshua E Flack

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Juliusz Mieszczanek

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Mariann Bienz

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    mb2@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7170-8706

Funding

Cancer Research UK (C7379/A24639)

  • Mariann Bienz

Medical Research Council (U105192713)

  • Mariann Bienz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Gammons et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Melissa V Gammons
  2. Miha Renko
  3. Joshua E Flack
  4. Juliusz Mieszczanek
  5. Mariann Bienz
(2020)
Feedback control of Wnt signaling based on ultrastable histidine cluster co-aggregation between Naked/NKD and Axin
eLife 9:e59879.
https://doi.org/10.7554/eLife.59879

Share this article

https://doi.org/10.7554/eLife.59879

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