nucleolin

Nucleolin is a multifunctional phosphoprotein primarily localized in the nucleolus of eukaryotic cells. Encoded by the NCL gene in humans, it is among the most abundant nonribosomal nucleolar proteins and plays a central role in ribosome biogenesis, chromatin organization, and RNA metabolism. Nucleolin can also be found in the nucleoplasm, cytoplasm, and, under certain conditions, on the cell surface, reflecting its ability to shuttle between compartments in response to cellular state.

Structurally, nucleolin is a modular protein composed of an acidic N-terminal domain, three RNA recognition motif (RRM) domains in the central region, and a glycine-arginine-rich GAR domain at the C-terminus. The acidic N-terminus mediates interactions with nucleolar components; the RRMs bind RNA and facilitate pre-rRNA processing; the GAR domain supports protein–protein interactions and nucleolar targeting. Nuclear localization signals and nucleolar localization sequences contribute to its predominant nucleolar residency.

Functionally, nucleolin participates in transcription of ribosomal RNA by RNA polymerase I, processing and maturation of pre-rRNA, and assembly and export of ribosomal subunits. It binds to rRNA and various RNA species, including mRNA, influencing RNA stability and translation in the cytoplasm. It also contributes to chromatin remodeling, DNA replication, and responses to DNA damage, reflecting broader roles in genome regulation and cell growth.

Regulation and interactions include modulation by phosphorylation, methylation, and acetylation across the cell cycle, and associations with ribosomal and non-ribosomal factors that coordinate ribosome production. Nucleolin interacts with pathways involving p53 and c-Myc and can influence proliferation and stress responses. On the cell surface, nucleolin participates in ligand binding and uptake and has been implicated in viral infection and cancer biology.

Clinically, nucleolin is often overexpressed in cancers and is investigated as a biomarker and potential therapeutic target due to its central role in cell growth and ribosome biogenesis.