1. Cell Biology

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

  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  Is a corresponding author
  1. University of Oxford, United Kingdom
https://doi.org/10.7554/eLife.81573
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Metrics

  • 2,053
    Page views
  • 329
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    Heat stress impairs centromere structure and segregation of meiotic chromosomes in Arabidopsis

    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.

    1. Cell Biology

    High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

    1. Cell Biology

    Golgi Apparatus: Making progress

    Jurgen Denecke
    Insight

    Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.