Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions

  1. Michael Rape  Is a corresponding author
  2. Achim Werner
  3. Regina Baur
  4. Nia Teerikorpi
  5. Deniz U. Kaya
  1. University of California Berkeley, United States
  2. National Institutes of Dental and Craniofacial Research, United States
  3. University of California, United States
  4. University of California, Berkeley, United States

Abstract

Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.

Data availability

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

Article and author information

Author details

  1. Michael Rape

    Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, United States
    For correspondence
    mrape@berkeley.edu
    Competing interests
    Michael Rape, Reviewing Editor, eLife. MR is founder and consultant to Nurix, a biotechnology company acting in the ubiquitin space. The work at Nurix does not overlap with the current study..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4849-6343
  2. Achim Werner

    NIDCR, National Institutes of Dental and Craniofacial Research, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. Regina Baur

    Molecular and Cell Biology, University of California, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5104-4888
  4. Nia Teerikorpi

    Molecular and Cell Biology, University of California, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Deniz U. Kaya

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4767-8655

Funding

Howard Hughes Medical Institute

  • Michael Rape
  • Regina Baur

National Institutes of Health (K99DE025314)

  • Achim Werner

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

Reviewing Editor

  1. Ivan Dikic, Goethe University Frankfurt, Germany

Publication history

  1. Received: January 25, 2018
  2. Accepted: July 7, 2018
  3. Accepted Manuscript published: July 12, 2018 (version 1)
  4. Accepted Manuscript updated: July 13, 2018 (version 2)
  5. Version of Record published: July 24, 2018 (version 3)

Copyright

© 2018, Rape 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. Michael Rape
  2. Achim Werner
  3. Regina Baur
  4. Nia Teerikorpi
  5. Deniz U. Kaya
(2018)
Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions
eLife 7:e35407.
https://doi.org/10.7554/eLife.35407
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