Details for: RNF123

Gene ID: 63891

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: RNF123

Ensembl ID: ENSG00000164068

Description: ring finger protein 123

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • melanocyte of skin CL1000458
    CSI 4.1
    rCSI 5.59%
    PRS 74.85
  • erythroblast CL0000765
    CSI 4.03
    rCSI 10.7%
    PRS 95.93
  • midzonal region hepatocyte CL0019028
    CSI 3.96
    rCSI 9.28%
    PRS 93.68
  • neural crest cell CL0011012
    CSI 3.87
    rCSI 3.06%
    PRS 93.41
  • ependymal cell CL0000065
    CSI 3.63
    rCSI 7.36%
    PRS 84.63
  • secretory cell CL0000151
    CSI 3.48
    rCSI 3.63%
    PRS 95.73
  • early lymphoid progenitor CL0000936
    CSI 3.19
    rCSI 2.81%
    PRS 97.93
  • erythrocyte CL0000232
    CSI 2.83
    rCSI 6.41%
    PRS 94.67
  • colonocyte CL1000347
    CSI 2.4
    rCSI 3.44%
    PRS 94.81
  • hepatocyte CL0000182
    CSI 2.34
    rCSI 4.19%
    PRS 94.73
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.29
    rCSI 2.95%
    PRS 90.45
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.16
    rCSI 2.69%
    PRS 88.03
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.08
    rCSI 4.67%
    PRS 89.97
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.04
    rCSI 3.42%
    PRS 89.72
  • centrilobular region hepatocyte CL0019029
    CSI 1.82
    rCSI 4.75%
    PRS 92.81
  • basal cell of epidermis CL0002187
    CSI 1.79
    rCSI 3.18%
    PRS 74.36
  • peripheral nervous system neuron CL2000032
    CSI 1.71
    rCSI 2.34%
    PRS 92.86
  • suprabasal keratinocyte CL4033013
    CSI 1.23
    rCSI 2.01%
    PRS 74.9
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.99
    rCSI 3.73%
    PRS 89.6
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.97
    rCSI 2.35%
    PRS 88.01
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.84
    rCSI 3.01%
    PRS 88.23
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.78
    rCSI 2.45%
    PRS 91.54
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.74
    rCSI 2.3%
    PRS 90.35
  • primitive red blood cell CL0002355
    CSI 0.71
    rCSI 3.83%
    PRS 96.57
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.45
    rCSI 2.63%
    PRS 89.86

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [RNF123](/details-gene/63891), or Ring Finger Protein 123, is a protein-coding gene located on chromosome 3p21.31. It functions as an E3 ubiquitin ligase, a key component of the ubiquitin-proteasome system responsible for protein degradation. Its primary molecular function involves '[Ubiquitin-protein transferase activity](/details-go/GO0004842)', facilitating the attachment of ubiquitin to target proteins, thereby marking them for proteolysis. This activity implicates [RNF123](/details-gene/63891) in fundamental cellular processes, including protein maturation, cell cycle regulation, and antigen presentation via the '[Class i mhc mediated antigen processing & presentation](/details-reactome/R-HSA-983169)' pathway. Notably, it is known to regulate the processing of NF-kappaB1 p105 to its active p50 subunit and the degradation of the cell cycle inhibitor p27(Kip1) ([Link](https://doi.org/10.1016/j.cell.2015.03.001), [Link](https://doi.org/10.1038/ncb1194)). Expression data suggests its significance across a diverse range of cell types, including [melanocyte of skin](/details-cell/CL1000458), [erythroblast](/details-cell/CL0000765), and various neuronal populations, pointing to a broad role in maintaining cellular proteostasis. ## Cellular Roles and Expression Landscape The expression profile of [RNF123](/details-gene/63891) indicates a broad and significant role across multiple, distinct cellular lineages rather than marking a single cell type. **Overall**, its highest significance is observed in a functionally diverse set of cells. These include pigment-producing cells like [melanocyte of skin](/details-cell/CL1000458) (CSI: 4.10), hematopoietic progenitors such as [erythroblast](/details-cell/CL0000765) (CSI: 4.03), and metabolically active liver cells, including [midzonal region hepatocyte](/details-cell/CL0019028) (CSI: 3.96). This suggests a fundamental role in processes common to cells with high rates of protein synthesis and turnover. Furthermore, [RNF123](/details-gene/63891) shows notable significance in the nervous system. It is a key gene in developmental lineages such as [neural crest cell](/details-cell/CL0011012) (CSI: 3.87) and specialized glial cells like [ependymal cell](/details-cell/CL0000065) (CSI: 3.63). Its importance extends to mature neurons, including [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 2.29) and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 2.16), as well as supportive cells like [astrocyte of the cerebral cortex](/details-cell/CL0002605) (CSI: 2.08). This widespread expression across different neural cell types may indicate a housekeeping function in maintaining protein quality control within the central nervous system. The gene's activity in [early lymphoid progenitor](/details-cell/CL0000936) (CSI: 3.19) is also consistent with its established role in the immune system. ## Pathways and Molecular Function The functional annotations for [RNF123](/details-gene/63891) confirm its role as a key regulator of protein stability and turnover. Its molecular functions are centered on '[Ubiquitin protein ligase activity](/details-go/GO0061630)' and '[Protein binding](/details-go/GO0005515)', enabling it to specifically target substrates for degradation. This core activity drives several critical biological processes, most prominently the '[Ubiquitin-dependent protein catabolic process](/details-go/GO0006511)'. This is reflected in its involvement in the broader Reactome pathway '[Metabolism of proteins](/details-reactome/R-HSA-392499)'. Functionally, this has been shown to be critical for cell cycle control through the regulation of p27(Kip1) degradation at the G1 phase ([Link](https://doi.org/10.1128/mcb.25.21.9292-9303.2005)). [RNF123](/details-gene/63891) also plays a significant role within the '[Immune system](/details-reactome/R-HSA-168256)'. It is a component of the '[Antigen processing: ubiquitination & proteasome degradation](/details-reactome/R-HSA-983168)' pathway, which is essential for generating peptides for MHC class I presentation. Moreover, research has identified [RNF123](/details-gene/63891) (also known as KPC1) as the E3 ligase responsible for processing the NF-kappaB1 precursor p105 into the active p50 subunit, a process that can suppress tumor growth ([Link](https://doi.org/10.1016/j.cell.2015.03.001)). Interestingly, some studies suggest [RNF123](/details-gene/63891) may also have E3 ligase-independent functions, for example in RIG-I-like receptor-mediated antiviral signaling, adding another layer of complexity to its molecular roles ([Link](https://doi.org/10.15252/embr.201541703)). ## Research Directions The function of [RNF123](/details-gene/63891) as a tumor-suppressive E3 ligase that modulates NF-kappaB signaling and protein stability presents several avenues for future research. **Testable Hypotheses:** 1. **Role in Melanoma Immune Evasion:** Given its top significance score in [melanocyte of skin](/details-cell/CL1000458) and its known role in processing NF-kappaB1 to generate tumor-suppressive p50 homodimers ([Link](https://doi.org/10.1073/pnas.2019604117)), we hypothesize that loss-of-function mutations or epigenetic silencing of [RNF123](/details-gene/63891) in melanoma cells leads to reduced p50 production, aberrant canonical NF-kappaB activation, and subsequent upregulation of immune checkpoint molecules like PD-L1, thereby promoting immune escape. 2. **Function in Erythropoiesis:** The high significance of [RNF123](/details-gene/63891) in [erythroblast](/details-cell/CL0000765) suggests a critical role in red blood cell development. We hypothesize that [RNF123](/details-gene/63891) is essential for the timely degradation of specific proteins (e.g., transcription factors or cell cycle regulators) that must be cleared to allow for terminal differentiation and enucleation of erythroblasts. 3. **Involvement in Neurodegeneration:** The gene's significant expression across multiple neuronal and glial cell types suggests a role in neuronal proteostasis. We hypothesize that age-related decline in [RNF123](/details-gene/63891) activity could be a contributing factor to neurodegenerative diseases characterized by protein aggregation, such as Alzheimer's or Parkinson's disease, by impairing the clearance of misfolded proteins. **Proposed Experiment:** To test the first hypothesis regarding melanoma immune evasion, one could perform a CRISPR-Cas9-mediated knockout of [RNF123](/details-gene/63891) in a human melanoma cell line. The impact on NF-kappaB signaling would be assessed by measuring the ratio of p105 to p50 via Western blot. Surface expression of PD-L1 would be quantified using flow cytometry. To assess the functional consequence, these modified melanoma cells would be co-cultured with activated human T cells, and T-cell proliferation, cytokine production (e.g., IFN-gamma), and cancer cell lysis would be measured to determine if loss of [RNF123](/details-gene/63891) confers resistance to immune-mediated killing. **Therapeutic Potential:** [RNF123](/details-gene/63891) represents a compelling therapeutic target, particularly in oncology. As its activity often leads to tumor suppression through the generation of p50, therapeutic strategies should focus on **activation or enhancement** of its function rather than inhibition. The development of small molecules that allosterically activate [RNF123](/details-gene/63891) or specifically enhance its interaction with the NF-kappaB1 p105 substrate could restore its tumor-suppressive effects in cancers where its function is compromised. Indeed, the concept of using a Proteolysis Targeting Chimera (PROTAC)-like molecule to bring p105 and [RNF123](/details-gene/63891) together has already been proposed as a viable anti-cancer strategy ([Link](https://doi.org/10.1073/pnas.2117254118)).

Genular Protein ID: 769493361

Symbol: RN123_HUMAN

Name: RING finger protein 123

UniProtKB Accession Codes:

Q5XPI4 A1L4Q3 A6NLS5 Q5I022 Q6PFW4 Q71RH0 Q8IW18 Q9H0M8 Q9H5L8 Q9H9T2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CORUM 1 CTD 1 ChEBI 8 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 10 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 10 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 2 RefSeq 4 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 2 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 15531880

Title: Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase.

PubMed ID: 15531880

DOI: 10.1038/ncb1194

PubMed ID: 16641997

Title: The DNA sequence, annotation and analysis of human chromosome 3.

PubMed ID: 16641997

DOI: 10.1038/nature04728

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15498874

Title: Large-scale cDNA transfection screening for genes related to cancer development and progression.

PubMed ID: 15498874

DOI: 10.1073/pnas.0404089101

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 11230166

Title: Towards a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.

PubMed ID: 11230166

DOI: 10.1101/gr.gr1547r

PubMed ID: 16227581

Title: Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle.

PubMed ID: 16227581

DOI: 10.1128/mcb.25.21.9292-9303.2005

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 25860612

Title: KPC1-mediated ubiquitination and proteasomal processing of NF-kappaB1 p105 to p50 restricts tumor growth.

PubMed ID: 25860612

DOI: 10.1016/j.cell.2015.03.001

PubMed ID: 27312109

Title: RNF123 has an E3 ligase-independent function in RIG-I-like receptor-mediated antiviral signaling.

PubMed ID: 27312109

DOI: 10.15252/embr.201541703

PubMed ID: 33168738

Title: Excess of the NF-kB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1- and chemokines-mediated mechanisms.

PubMed ID: 33168738

DOI: 10.1073/pnas.2019604117

PubMed ID: 34873064

Title: A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-kappaB1 p105 to p50: A potential for a tumor-suppressive PROTAC.

PubMed ID: 34873064

DOI: 10.1073/pnas.2117254118

Sequence Information:

  • Length: 1314
  • Mass: 148515
  • Checksum: A0F8F4D68EAFB8E1
  • Sequence:
    • MASKGAGMSF SRKSYRLTSD AEKSRVTGIV QEKLLNDYLN RIFSSSEHAP PAATSRKPLN 
FQNLPEHLDQ LLQVDNEEEE SQGQVEGRLG PSTVVLDHTG GFEGLLLVDD DLLGVIGHSN 
FGTIRSTTCV YKGKWLYEVL ISSQGLMQIG WCTISCRFNQ EEGVGDTHNS YAYDGNRVRK 
WNVTTTNYGK AWAAGDIVSC LIDLDDGTLS FCLNGVSLGT AFENLSRGLG MAYFPAISLS 
FKESVAFNFG SRPLRYPVAG YRPLQDPPSA DLVRAQRLLG CFRAVLSVEL DPVEGRLLDK 
ESSKWRLRGQ PTVLLTLAHI FHHFAPLLRK VYLVEAVLMS FLLGIVEKGT PTQAQSVVHQ 
VLDLLWLFME DYEVQDCLKQ LMMSLLRLYR FSPIVPDLGL QIHYLRLTIA ILRHEKSRKF 
LLSNVLFDVL RSVVFFYIKS PLRVEEAGLQ ELIPTTWWPH CSSREGKEST EMKEETAEER 
LRRRAYERGC QRLRKRIEVV EELQVQILKL LLDNKDDNGG EASRYIFLTK FRKFLQENAS 
GRGNMPMLCP PEYMVCFLHR LISALRYYWD EYKASNPHAS FSEEAYIPPQ VFYNGKVDYF 
DLQRLGGLLS HLRKTLKDDL ASKANIVIDP LELQSTAMDD LDEDEEPAPA MAQRPMQALA 
VGGPLPLPRP GWLSSPTLGR ANRFLSTAAV SLMTPRRPLS TSEKVKVRTL SVEQRTREDI 
EGSHWNEGLL LGRPPEEPEQ PLTENSLLEV LDGAVMMYNL SVHQQLGKMV GVSDDVNEYA 
MALRDTEDKL RRCPKRRKDI LAELTKSQKV FSEKLDHLSR RLAWVHATVY SQEKMLDIYW 
LLRVCLRTIE HGDRTGSLFA FMPEFYLSVA INSYSALKNY FGPVHSMEEL PGYEETLTRL 
AAILAKHFAD ARIVGTDIRD SLMQALASYV CYPHSLRAVE RIPEEQRIAM VRNLLAPYEQ 
RPWAQTNWIL VRLWRGCGFG YRYTRLPHLL KTKLEDANLP SLQKPCPSTL LQQHMADLLQ 
QGPDVAPSFL NSVLNQLNWA FSEFIGMIQE IQQAAERLER NFVDSRQLKV CATCFDLSVS 
LLRVLEMTIT LVPEIFLDWT RPTSEMLLRR LAQLLNQVLN RVTAERNLFD RVVTLRLPGL 
ESVDHYPILV AVTGILVQLL VRGPASEREQ ATSVLLADPC FQLRSICYLL GQPEPPAPGT 
ALPAPDRKRF SLQSYADYIS ADELAQVEQM LAHLTSASAQ AAAASLPTSE EDLCPICYAH 
PISAVFQPCG HKSCKACINQ HLMNNKDCFF CKTTIVSVED WEKGANTSTT SSAA