期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.81573
关键词
endoplasmic reticulum; nuclear envelope; ERAD; SUN2; protein quality control; ubiquitin; Human
类别
资金
- European Research Council [817708]
- Wellcome Trust [223153/Z/21/Z]
- Cancer Research UK [DRCNPG-Nov21\100004]
- Medical Research Council [MR/K006703/1]
- Edward Penley Abraham Fund [RF 280]
- European Research Council (ERC) [817708] Funding Source: European Research Council (ERC)
- Wellcome Trust [223153/Z/21/Z] Funding Source: Wellcome Trust
This article describes a mechanism of regulated degradation of SUN2, an inner nuclear membrane protein. The study found that the binding of SUN2 to the ubiquitin ligase SCF beta TrCP is regulated by Casein Kinase 2 and CTDNEP1. The degradation of SUN2 via this mechanism is important for maintaining normal nuclear architecture.
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-Box(beta TrCP) (SCF beta TrCP). Upon binding to phosphorylated SUN2, SCF beta TrCP 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.
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