Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function
- University of Oxford, United Kingdom
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.
Article and author information
Author details
Logesvaran Krshnan
Michael Van de Weijer
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.
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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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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