N4BP1

Official Full Name

NEDD4 binding protein 1

Organism

Homo sapiens

GeneID

9683

Background

Enables RNA nuclease activity; mRNA binding activity; and ubiquitin binding activity. Involved in cellular response to UV and negative regulation of viral genome replication. Predicted to be located in cytosol and nucleolus. Predicted to be active in PML body. [provided by Alliance of Genome Resources, Feb 2025]

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Detailed Information

Ubiquitination is accomplished through sequential actions of the E1, E2, and E3 enzymes. E3 ubiquitin ligases are the enzymes responsible for the transfer of ubiquitin to a specific protein substrate. NEDD4 binding protein 1 (N4BP1) has been identified as a protein interactor and a substrate of the homologous to E6AP C terminus (HECT) domain-containing E3 ubiquitin–protein ligase (E3), Nedd4. More specific, N4BP1 is the inhibitor of the E3 ubiquitin-protein ligase Itchy homolog (ITCH). N4BP1 primarily localizes to the nucleolus and also localizes to the PML nuclear bodies, when desumoylated. In the body, N4BP1 is detected in heart, lung, brain, liver, skeletal muscle, pancreas, kidney, spleen, testis and ovary ^[1].

Post-translational modification

N4BP1 will be monoubiquitinated by NEDD4.
N4BP1 will be polyubiquitinated, resulting to its degradation by the proteasome.
N4BP1 will be sumoylated with SUMO1, abrogating polyubiquitination and subsequent degradation.
N4BP1 will be desumoylated by SENP1, leading to accumulation in PML nuclear bodies.

Figure 1. Model of N4BP1 post-translational modification and turnover ^[2].

The biological process that N4BP1 get involved

N4BP1 responses to UV;
N4BP1 negative regulates proteasomal ubiquitin-dependent protein catabolic process;
N4BP1 negative regulates protein ubiquitination.

Function

N4BP1 specifically associates with the WW domain-containing central region of ITCH and both N4BP1 and p73α interact with the WW2 domain of ITCH. As a consequence, N4BP1 strongly inhibits Itch-catalyzed polyubiquitylation by preventing the interaction with its substrates, thereby reducing the transfer of ubiquitin molecules to ITCH protein targets. Hence, N4BP1 interferes via the proteolytic pathway of both p73α and c-Jun, resulting of protein stabilization and increased transcriptional activity.

Research meaning

The identification of N4BP1 as a specific inhibitor of ITCH-mediated ubiquitylation of tumor suppressor molecules may provide an alternative means to selectively block ITCH function and thereby regulate tumor progression and the response of cancer cells to chemotherapy. Developing therapeutic approaches for cancer treatment targeting protein degradation is currently an attractive research avenue. An effective therapeutic approach would be targeting specific components of the ubiquitin system, such as the E3 enzymes. For instance, the inhibition of the E3 activity of Itch could be used to increase chemosensitivity of tumor cells by selectively up-regulating p73, p63, and c-Jun basal protein levels. The importance of ITCH down-regulation becomes evident in response to DNA damage-based chemotherapeutic drugs, in which reduction of its protein levels leads to p73α stabilization and increased proapoptotic function ^[3]. Previous study found that miR‑28‑5p downregulated N4BP1 mRNA and protein expression in human ovarian cancer. Their study indicated that miR‑28‑5p promoted the progression of ovarian cancer cell cycle, proliferation, migration and invasion, inhibited apoptosis, and induced the process of EMT through inhibition of N4BP1 in vitro ^{[4, 5]}.

Conclusions

N4BP1 is the first nucleolar protein identified whose regulation fits this newly emerging function for PML NBs. In conclusion, the detailed characterization of N4BP1 presented in previous studies indicates that localization to PML NBs and turnover are tightly linked and regulated by the dynamic interplay of post-translational modification by both ubiquitin and SUMO, which are both essential protein modification for living activity.

References:

Ishikawa, K., et al., Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res, 1998. 5(3): p. 169-76.
Sharma, P., et al., N4BP1 is a newly identified nucleolar protein that undergoes SUMO-regulated polyubiquitylation and proteasomal turnover at promyelocytic leukemia nuclear bodies. J Cell Sci, 2010. 123(Pt 8): p. 1227-34.
Oberst, A., et al., The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch. Proc Natl Acad Sci U S A, 2007. 104(27): p. 11280-5.
Xu, J., et al., miR-28-5p promotes the development and progression of ovarian cancer through inhibition of N4BP1. Int J Oncol, 2017.
Rizzo, M., et al., The miRNA Pull Out Assay as a Method to Validate the miR-28-5p Targets Identified in Other Tumor Contexts in Prostate Cancer. Int J Genomics, 2017. 2017: p. 5214806.

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