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

Logesvaran Krshnan, Wingyan Skyla Siu, Michael Van de Weijer, Daniel Hayward, Elena Navarro Guerrero, Ulrike Gruneberg, Pedro Carvalho

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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 2 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.

Original languageEnglish
JournaleLife
Volume11
DOIs
Publication statusPublished - 1 Nov 2022

Keywords

  • cell biology
  • endoplasmic reticulum
  • ERAD
  • human
  • nuclear envelope
  • protein quality control
  • SUN2
  • ubiquitin

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