1. Gene Aliases

Neuralized E3 Ubiquitin Protein Ligase 3, RNF132, Lincr, Lung-Inducible Neuralized-Related C3CH4 RING Domain Protein, RING-Type E3 Ubiquitin Transferase NEURL3, E3 Ubiquitin-Protein Ligase NEURL3, Neuralized-Like Protein 3, LOC93082, Neuralized Homolog 3 (Drosophila) Pseudogene, Neuralized Homolog 3 Pseudogene, EC 2.3.2.27, LINCR

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=NEURL3&keywords=Neurl3]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

innate immune response [Innate immune responses are defense responses mediated by germline encoded components that directly recognize components of potential pathogens. GO:0045087]

protein ubiquitination [The process in which one or more ubiquitin groups are added to a protein. GO:0016567]

ubiquitin-dependent endocytosis [Endocytosis of a protein that requires the substrate to be modified by ubiquitination. Several plasma membrane proteins, including cell surface permeases and some receptors, are targeted for internalization by endocytosis, and are thereafter delivered to the vacuole or lysosome, where they are degraded. GO:0070086]

MSigDB Signatures:

MEBARKI_HCC_PROGENITOR_FZD8CRD_DN: Transcriptome of human HepaRG hepatocellular carcinoma liver progenitors in responses to a WNT3A-enriched microenvironment and dissection of pathways dependent on _-catenin and/or blocked by the SFRP-like Wnt inhibitor FZD8_CRD. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/MEBARKI_HCC_PROGENITOR_FZD8CRD_DN.html]

CERVERA_SDHB_TARGETS_1_UP: Genes turned on in Hep3B cells (hepatocellular carcinoma, HCC) upon knockdown of SDHB [GeneID=6390] by RNAi. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CERVERA_SDHB_TARGETS_1_UP.html]

KRIEG_HYPOXIA_NOT_VIA_KDM3A: Genes induced under hypoxia independently of KDM3A [GeneID=55818] in RCC4 cells (renal carcinoma) expressing VHL [GeneID=7428]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KRIEG_HYPOXIA_NOT_VIA_KDM3A.html]

7. Gene Descriptions

NCBI Gene Summary: Predicted to enable ubiquitin protein ligase activity. Predicted to act upstream of or within protein ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

GeneCards Summary: NEURL3 (Neuralized E3 Ubiquitin Protein Ligase 3) is a Protein Coding gene. Diseases associated with NEURL3 include Hepatitis C Virus. Among its related pathways are 2q11.2 copy number variation syndrome. Gene Ontology (GO) annotations related to this gene include ligase activity and ubiquitin-protein transferase activity. An important paralog of this gene is NEURL1B.

UniProtKB/Swiss-Prot Summary: E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.

8. Cellular Location of Gene Product

Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000163121/subcellular]

9. Mechanistic Information

Summary

NEURL3 serves as an E3 ubiquitin-protein ligase catalyzing K63-linked ubiquitination of IRF7, leading to transcriptional activation of interferon-stimulated genes crucial for antiviral defense [CS: 8]. Its dysregulation in liver diseases is mechanistically linked to its role in innate immunity and viral assembly inhibition [CS: 6]. Upregulation of NEURL3 in response to liver injury or inflammation, such as caused by nonalcoholic steatohepatitis (NASH), is driven by NF-kappaB signaling in the presence of inflammatory factors like LPS, TNF-alpha, and IFN-gamma [CS: 7]. This upregulation suggests a protective hepatic response, as NEURL3-mediated ubiquitination processes could diminish viral hijacking of the liver cells and decrease inflammation [CS: 7].

NEURL3 dysregulation occurs in liver diseases such as nonalcoholic steatohepatitis (NASH), where its mRNA expression correlates with the severity of liver damage [CS: 8]. Increased NEURL3 expression in these conditions could reflect a host response to counteract ongoing liver cell stress or injury, potentially through its ubiquitin ligase activity that aids in clearing damaged proteins or regulating signaling pathways vital for cell survival [CS: 6]. Specifically, the direct binding of NEURL3 to the HCV E1 envelope glycoprotein, impeding its interaction with E2 and inhibiting virus assembly, demonstrates a hepatoprotective mechanism against hepatitis C virus infection [CS: 5]. However, the hypermethylation and reduced expression of NEURL3 in nasopharyngeal carcinoma suggest that in certain pathologies, the loss of NEURL3-mediated degradation of vimentin, a protein involved in cell adhesion and migration, could favor disease progression by allowing cellular processes like epithelial-mesenchymal transition and metastasis [CS: 6].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: kidney, pancreas, salivary gland (group enriched) [https://www.proteinatlas.org/ENSG00000163121/tissue]

Cell type enchanced: basal respiratory cells, collecting duct cells, ductal cells, exocrine glandular cells, ionocytes, pancreatic endocrine cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000163121/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

No DisGenNet altered expression associations were found for Neurl3 and diseases associated with Liver