E3 ubiquitin ligase RNF123 targets lamin B1 and lamin-binding proteins.

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Lamins are crucial nuclear proteins maintaining nuclear structure and function.
• Mutations in lamins lead to laminopathies, a group of genetic disorders.
• RNF123, an E3 ubiquitin ligase, is upregulated in cells with lamin A mutations, but its role is unclear.

Purpose of the Study:

• To investigate the functional relevance of RNF123 in laminopathic cells.
• To identify RNF123-interacting proteins and understand its mechanism of action.
• To explore the impact of RNF123 on nuclear protein stability and cell cycle progression in the context of laminopathies.

Main Methods:

• Mass spectrometry-based proteomics to identify RNF123-interacting proteins.
• Ubiquitination and proteasomal degradation assays.
• Cellular studies using lamin A rod domain mutants and RNF123 overexpression/coexpression systems.

Main Results:

• Identified retinoblastoma protein (pRb), lamina-associated polypeptide 2α (LAP2α), and emerin as RNF123 interactors.
• Demonstrated that RNF123 mediates ubiquitination and proteasomal degradation of pRb, LAP2α, and lamin B1.
• Observed similar degradation of these proteins in cells with lamin A rod domain mutants (G232E, Q294P, R386K).
• Showed that RNF123 overexpression causes S-phase delay, which is rescued by coexpressing pRb or LAP2α.

Conclusions:

• RNF123-mediated ubiquitination and degradation of lamin-binding proteins contribute to laminopathies.
• Depletion of nuclear proteins and cell cycle defects are potential consequences of RNF123 activity in these diseases.
• RNF123 represents a potential therapeutic target for managing laminopathies.