Nucleolin is an abundant protein found in eukaryotic cells, including animals, plants, and yeast. Primarily located in the nucleolus, a dense structure within the cell’s nucleus, it also exists in the nucleoplasm, cytoplasm, and on the cell surface. This protein is multifunctional, with roles varying by location and cellular conditions. Its structure and functions are conserved across diverse species.
Multifaceted Cellular Roles
Nucleolin performs many functions within healthy cells, with a significant role in ribosome biogenesis. In the nucleolus, it participates in the synthesis and processing of precursor ribosomal RNA (pre-rRNA) into mature ribosomal RNA (rRNA). These molecules then assemble with ribosomal proteins to form 40S and 60S ribosomal subunits, essential for protein synthesis.
The protein also contributes to chromatin remodeling and gene expression. Nucleolin acts as a histone chaperone, influencing chromatin structure by destabilizing histone octamers and transferring histone dimers, particularly H2A-H2B. This activity enhances chromatin remodeling complexes, regulating DNA accessibility for transcription. Nucleolin is involved in regulating RNA polymerase I transcription of ribosomal DNA and can facilitate transcription through nucleosomes, similar to the FACT complex.
Nucleolin has emerging functions in DNA replication and repair. Present in the nucleoplasm, it is recruited to sites of DNA damage, interacting with factors like γH2AX, RPA32, and PCNA following replication stress. Nucleolin contributes to homologous recombination repair by mediating nucleosome disruption, allowing DNA repair proteins to access damaged DNA. This suggests a role in maintaining genomic stability, especially under replication stress.
Nucleolin’s presence extends beyond the nucleus, with functions in the cytoplasm and on the cell surface. In the cytoplasm, it influences mRNA stability and translation by binding to messenger RNAs. It is also implicated in the formation of stress granules, temporary compartments that sequester stalled mRNAs during environmental challenges. On the cell surface, nucleolin acts as a receptor for extracellular ligands, participating in cell adhesion, signaling, and molecule internalization.
Involvement in Disease
Nucleolin’s altered behavior is linked to various disease states, particularly cancer. In many cancers, nucleolin is often overexpressed or aberrantly localized on the cell surface or in the cytoplasm. This abnormal expression correlates with increased malignancy and poorer patient outcomes in cancers like hepatocellular carcinoma and some breast cancers.
Nucleolin contributes to diverse cancer hallmarks. It promotes cell proliferation by stabilizing pro-tumorigenic mRNAs, including anti-apoptotic proteins and epidermal growth factor receptor (EGFR). It also inhibits programmed cell death (apoptosis) by blocking pro-apoptotic factors like the Fas receptor, preventing FasL interaction.
Nucleolin stimulates angiogenesis, new blood vessel formation that supplies tumors, by modulating related factors. On the cell surface, it binds ligands involved in tumorigenesis and angiogenesis, mediating their internalization. Nucleolin may also contribute to drug resistance in cancer cells.
Nucleolin also plays a role in viral infections, acting as a receptor or co-factor for viruses. It facilitates viral entry into host cells, as seen with single-stranded RNA viruses like respiratory syncytial virus (RSV), enterovirus A 71 (EVA71), and influenza A virus (IAV). Beyond entry, nucleolin aids later viral life cycle stages, such as replication and nucleo-cytoplasmic export of viral genomes. For example, in SARS-CoV-2 infection, nucleolin interacts with viral proteins and stress granule components, influencing viral proliferation and host cell apoptosis.
Therapeutic and Diagnostic Potential
Understanding nucleolin’s disease roles opens avenues for medical applications, particularly therapeutic targeting. In cancer, targeting nucleolin aims to inhibit its pro-cancerous functions or deliver drugs to tumor cells. Aptamers, synthetic nucleic acid molecules, are being developed for this purpose. AS1411, a well-studied nucleolin-targeting DNA aptamer, binds to cell surface nucleolin on cancer cells, inhibiting proliferation and promoting apoptosis. It can also deliver anticancer drugs or nanoparticles to tumor sites, improving drug accumulation and reducing systemic side effects.
Antibodies targeting nucleolin, especially its cell surface form, are also investigated. These antibodies block nucleolin’s activity, reducing tumor growth, angiogenesis, and increasing apoptosis. Small molecules are also explored to modulate nucleolin’s activity, interfering with its disease-supporting functions.
Nucleolin also shows promise as a diagnostic biomarker. Its altered expression and localization in cancers suggest potential for disease detection, monitoring, and therapy response prediction. Detecting nucleolin on cell surfaces or in bodily fluids offers a non-invasive way to assess disease status. For instance, nucleolin mRNA overexpression correlates with poor overall survival and predicted disease progression in lung adenocarcinoma and squamous carcinoma patients.