Journal
FEBS JOURNAL
Volume 285, Issue 12, Pages 2243-2262Publisher
WILEY
DOI: 10.1111/febs.14477
Keywords
laminopathy; nuclear lamina; nuclear organization; protein degradation; ubiquitination
Categories
Funding
- Council of Scientific and Industrial Research [BSC208]
- Department of Science and Technology, India
- University Grants Commission, India
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Lamins are key nuclear proteins which are important for maintaining nuclear structure and function. Mutations in lamins cause a spectrum of genetic diseases termed as laminopathies. RING finger containing E3 ubiquitin ligase, RNF123, is transcriptionally upregulated in cells expressing rod domain lamin A mutations. However, the functional relevance of RNF123 in laminopathic cells is not clear. Using a mass spectrometry-based approach, we identified lamins and lamin-binding proteins retinoblastoma protein (pRb), lamina-associated polypeptide 2 (LAP2), and emerin as RNF123-interacting proteins. We determined that RNF123 mediated the ubiquitination of these proteins and caused the proteasomal degradation of pRb, LAP2, and lamin B1. Furthermore, these proteins were also targeted for proteasomal degradation in cells expressing lamin A rod domain mutants G232E, Q294P, and R386K. Overexpression of RNF123 resulted in delayed transit through the S-phase which was alleviated by coexpression of pRb or LAP2. Our findings imply that RNF123-mediated ubiquitination of lamin-binding proteins may contribute to disease-causing mechanisms in laminopathies by depletion of key nuclear proteins and defects in cell cycle kinetics.
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