Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function

Abstract

Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) and inner nuclear membrane (INM) proteins. Mutations in INM proteins interfering with these interactions result in disease. However, mechanisms controlling the levels and turnover of INM proteins remain unknown. Here, we describe a mechanism of regulated degradation of the INM SUN domain-containing protein 2 (SUN2). We show that Casein Kinase II and the C-terminal domain Nuclear Envelope Phosphatase 1 (CTDNEP1) have opposing effects on SUN2 levels by regulating SUN2 binding to the ubiquitin ligase Skp/Cullin1/F-BoxβTrCP (SCFβTrCP). Upon binding to phosphorylated SUN2, SCFβTrCP promotes its ubiquitination. Ubiquitinated SUN2 is membrane extracted by the AAA ATPase p97 and delivered to the proteasome for degradation. Importantly, accumulation of non-degradable SUN2 results in aberrant nuclear architecture, vulnerability to DNA damage and increased lagging chromosomes in mitosis. These findings uncover a central role of proteolysis in INM protein homeostasis.

Data availability

Sequencing data has been deposited European Nucleotide Archive repository and has the accession number PRJEB54102.

The following data sets were generated

Article and author information

Author details

  1. Logesvaran Krshnan

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6281-1587
  2. Wingyan Skyla Siu

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Van de Weijer

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0954-0228
  4. Daniel Hayward

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Elena Navarro Guerrero

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Ulrike Gruneberg

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Pedro Carvalho

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    pedro.carvalho@path.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9691-5277

Funding

European Research Council (817708)

  • Pedro Carvalho

Wellcome Trust (223153/Z/21/Z)

  • Pedro Carvalho

Cancer Research UK Discovery Programme (DRCNPG-Nov21\100004)

  • Ulrike Gruneberg

Medical Research Council (MR/K006703/1)

  • Ulrike Gruneberg

Edward Penley Abraham Fund (RF 280)

  • Ulrike Gruneberg

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

Reviewing Editor

  1. Wade Harper, Harvard Medical School, United States

Version history

  1. Received: July 3, 2022
  2. Preprint posted: July 16, 2022 (view preprint)
  3. Accepted: October 12, 2022
  4. Accepted Manuscript published: November 1, 2022 (version 1)
  5. Version of Record published: November 14, 2022 (version 2)

Copyright

© 2022, Krshnan 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. Logesvaran Krshnan
  2. Wingyan Skyla Siu
  3. Michael Van de Weijer
  4. Daniel Hayward
  5. Elena Navarro Guerrero
  6. Ulrike Gruneberg
  7. Pedro Carvalho
(2022)
Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function
eLife 11:e81573.
https://doi.org/10.7554/eLife.81573

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https://doi.org/10.7554/eLife.81573

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