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    NPLOC4 NPL4 homolog, ubiquitin recognition factor [ Homo sapiens (human) ]

    Gene ID: 55666, updated on 10-Dec-2024

    Summary

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    Official Symbol
    NPLOC4provided by HGNC
    Official Full Name
    NPL4 homolog, ubiquitin recognition factorprovided by HGNC
    Primary source
    HGNC:HGNC:18261
    See related
    Ensembl:ENSG00000182446 MIM:606590; AllianceGenome:HGNC:18261
    Gene type
    protein coding
    RefSeq status
    VALIDATED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    NPL4
    Summary
    Predicted to enable ubiquitin binding activity and ubiquitin protein ligase binding activity. Predicted to contribute to K48-linked polyubiquitin modification-dependent protein binding activity and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in negative regulation of RIG-I signaling pathway; negative regulation of type I interferon production; and proteolysis involved in protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Dec 2024]
    Expression
    Ubiquitous expression in testis (RPKM 14.2), esophagus (RPKM 10.3) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See NPLOC4 in Genome Data Viewer
    Location:
    17q25.3
    Exon count:
    21
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (81556885..81637112, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (82474164..82554047, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 17 NC_000017.10 (79523911..79604138, complement)

    Chromosome 17 - NC_000017.11Genomic Context describing neighboring genes Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:79482073-79482696 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:79482697-79483322 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12967 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:79483947-79484572 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79484573-79485196 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9133 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9134 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12970 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12969 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79495325-79495851 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79495852-79496377 Neighboring gene fascin actin-bundling protein 2, retinal Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79504525-79505496 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79507853-79508353 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79516844-79517639 Neighboring gene FA core complex associated protein 100 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9135 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9136 Neighboring gene uncharacterized LOC124904085 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9137 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12971 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9138 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9139 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79520435-79521010 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79525737-79526238 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:79526239-79526738 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12972 Neighboring gene ReSE screen-validated silencer GRCh37_chr17:79537592-79537800 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12973 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12974 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:79585853-79586396 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:79586397-79586940 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9140 Neighboring gene tetraspanin 10 Neighboring gene phosphodiesterase 6G

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma. Wang N, et al. Sci Rep, 2023 Nov 22. PMID 37993584, Free PMC Article
    2. Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma. Yoshino H, et al. PLoS One, 2020. PMID 32667929, Free PMC Article
    3. Ufd1-Npl4 is a negative regulator of cholera toxin retrotranslocation. McConnell E, et al. Biochem Biophys Res Commun, 2007 Apr 20. PMID 17331469
    4. Mechanistic insight into substrate processing and allosteric inhibition of human p97. Pan M, et al. Nat Struct Mol Biol, 2021 Jul. PMID 34262183
    5. Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA. Lu BS, et al. Cancer Cell Int, 2019. PMID 31164795, Free PMC Article

    See all (155) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma.
      Title: NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma.
    2. Structural basis for the interaction between human Npl4 and Npl4-binding motif of human Ufd1.
      Title: Structural basis for the interaction between human Npl4 and Npl4-binding motif of human Ufd1.
    3. Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.
      Title: Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.
    4. Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.
      Title: Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.
    5. Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma.
      Title: Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma.
    6. Multisystem proteinopathy mutations in VCP/p97 increase NPLOC4-UFD1L binding and substrate processing.
      Title: Multisystem Proteinopathy Mutations in VCP/p97 Increase NPLOC4·UFD1L Binding and Substrate Processing.
    7. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation.
      Title: Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy.
    8. The study revealed a regulatory role of the p97-Npl4-Ufd1 complex in regulating a partial degradation of the NF-kappaB subunit p100.
      Title: The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-κB Signaling via Partial Degradation of the NF-κB Subunit p100.
    9. p97-Ufd1-Npl4 is an integral part of G2/M checkpoint signaling and thereby suppresses chromosome instability.
      Title: The p97-Ufd1-Npl4 ATPase complex ensures robustness of the G2/M checkpoint by facilitating CDC25A degradation.
    10. Data indicate that the p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IkappaBalpha via the interactions between p97 and the SCF(beta-TRCP) ubiquitin ligase.
      Title: The p97-UFD1L-NPL4 protein complex mediates cytokine-induced IκBα proteolysis.
    Submit: New GeneRIF Correction See all GeneRIFs (16)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    EBI GWAS Catalog

    Description
    Digital quantification of human eye color highlights genetic association of three new loci.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Vpu vpu The VCP-UFD1L-NPL4 complex is required for HIV-1 Vpu-induced CD4 degradation in the ER-associated degradation pathway. The ATPase activity of VCP and ubiquitin binding to UFD1L are important for CD4 degradation by Vpu PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ14336, FLJ20657, FLJ23742, KIAA1499

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATPase binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables K48-linked polyubiquitin modification-dependent protein binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables K63-linked polyubiquitin modification-dependent protein binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein-containing complex binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables ubiquitin binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables ubiquitin protein ligase binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Process Evidence Code Pubs
    involved_in ERAD pathway ISO
    Inferred from Sequence Orthology
    more info
    		  
    involved_in Golgi organization ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    involved_in negative regulation of RIG-I signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in negative regulation of type I interferon production IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in proteasome-mediated ubiquitin-dependent protein catabolic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in retrograde protein transport, ER to cytosol IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in retrograde protein transport, ER to cytosol ISO
    Inferred from Sequence Orthology
    more info
    		  
    involved_in ubiquitin-dependent protein catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in ubiquitin-dependent protein catabolic process IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    part_of UFD1-NPL4 complex IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    part_of VCP-NPL4-UFD1 AAA ATPase complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    part_of VCP-NPL4-UFD1 AAA ATPase complex IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    part_of VCP-NPL4-UFD1 AAA ATPase complex ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  
    located_in endoplasmic reticulum ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    located_in nuclear outer membrane-endoplasmic reticulum membrane network ISS
    Inferred from Sequence or Structural Similarity
    more info
    		 PubMed 
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
    		  
    located_in nucleus HDA PubMed 
    is_active_in nucleus IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  

    General protein information

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    Preferred Names
    nuclear protein localization protein 4 homolog
    Names
    NPLOC4 ubiquitin recognition factor
    nuclear protein localization 4 homolog

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001369698.1 → NP_001356627.1  nuclear protein localization protein 4 homolog isoform 2

      Status: VALIDATED

      Source sequence(s)
      AC137896, AC139530
      UniProtKB/TrEMBL
      A0A994J7H4
      Conserved Domains (5) summary
      smart00547
      Location:589 → 611
      ZnF_RBZ; Zinc finger domain
      sd00029
      Location:589 → 608
      zf-RanBP2; RanBP2-type Zn finger [structural motif]
      pfam05021
      Location:249 → 561
      NPL4; NPL4 family
      pfam05020
      Location:105 → 245
      zf-NPL4; NPL4 family, putative zinc binding region
      pfam11543
      Location:1 → 80
      UN_NPL4; Nuclear pore localization protein NPL4

    2. NM_017921.4 → NP_060391.2  nuclear protein localization protein 4 homolog isoform 1

      See identical proteins and their annotated locations for NP_060391.2

      Status: VALIDATED

      Description
      Transcript Variant: This variant (1) encodes isoform 1.
      Source sequence(s)
      AB040932, AC137896, AK000664, BC025930, HY116973
      Consensus CDS
      CCDS45812.1
      UniProtKB/Swiss-Prot
      Q8N3J1, Q8TAT6, Q9H8V2, Q9H964, Q9NWR5, Q9P229
      UniProtKB/TrEMBL
      A0A994J7H4
      Related
      ENSP00000331487.5, ENST00000331134.11
      Conserved Domains (5) summary
      COG5100
      Location:5 → 560
      NPL4; Nuclear pore protein [Nuclear structure]
      sd00029
      Location:584 → 603
      zf-RanBP2; RanBP2-type Zn finger [structural motif]
      pfam05020
      Location:105 → 245
      zf-NPL4; NPL4 family, putative zinc binding region
      pfam05021
      Location:249 → 556
      NPL4; NPL4 family
      pfam11543
      Location:1 → 80
      UN_NPL4; Nuclear pore localization protein NPL4

    RNA

    1. NR_130139.1 RNA Sequence

      Status: VALIDATED

      Source sequence(s)
      AC137896, AK000664, BU542911, CK903591, HY179409

    2. NR_130140.2 RNA Sequence

      Status: VALIDATED

      Description
      Transcript Variant: This variant (3) lacks multiple 5' exons and contains an alternate 5' terminal exon, compared to variant 1. This variant is represented as non-coding because it lacks a large portion of the coding region, including the translational start codon, found in variant 1.
      Source sequence(s)
      AC137896, AK000664, DA998574

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000017.11 Reference GRCh38.p14 Primary Assembly

      Range
      81556885..81637112 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047436365.1 → XP_047292321.1  nuclear protein localization protein 4 homolog isoform X3

      UniProtKB/TrEMBL
      A0A994J7H4

    2. XM_011524980.2 → XP_011523282.1  nuclear protein localization protein 4 homolog isoform X2

      UniProtKB/TrEMBL
      A0A994J7H4
      Conserved Domains (4) summary
      COG5100
      Location:5 → 564
      NPL4; Nuclear pore protein [Nuclear structure]
      pfam05020
      Location:105 → 245
      zf-NPL4; NPL4 family, putative zinc binding region
      pfam05021
      Location:249 → 561
      NPL4; NPL4 family
      pfam11543
      Location:1 → 80
      UN_NPL4; Nuclear pore localization protein NPL4

    3. XM_047436368.1 → XP_047292324.1  nuclear protein localization protein 4 homolog isoform X7

    4. XM_011524982.3 → XP_011523284.1  nuclear protein localization protein 4 homolog isoform X4

      UniProtKB/TrEMBL
      A0A994J7H4
      Conserved Domains (4) summary
      COG5100
      Location:5 → 564
      NPL4; Nuclear pore protein [Nuclear structure]
      pfam05020
      Location:105 → 245
      zf-NPL4; NPL4 family, putative zinc binding region
      pfam05021
      Location:249 → 561
      NPL4; NPL4 family
      pfam11543
      Location:1 → 80
      UN_NPL4; Nuclear pore localization protein NPL4

    5. XM_047436366.1 → XP_047292322.1  nuclear protein localization protein 4 homolog isoform X5

      UniProtKB/TrEMBL
      A0A994J7H4

    6. XM_011524979.2 → XP_011523281.1  nuclear protein localization protein 4 homolog isoform X1

      See identical proteins and their annotated locations for XP_011523281.1

      UniProtKB/TrEMBL
      A0A994J7H4
      Related
      ENSP00000363879.5, ENST00000374747.9
      Conserved Domains (4) summary
      COG5100
      Location:5 → 558
      NPL4; Nuclear pore protein [Nuclear structure]
      pfam05020
      Location:105 → 245
      zf-NPL4; NPL4 family, putative zinc binding region
      pfam05021
      Location:249 → 556
      NPL4; NPL4 family
      pfam11543
      Location:1 → 80
      UN_NPL4; Nuclear pore localization protein NPL4

    7. XM_047436367.1 → XP_047292323.1  nuclear protein localization protein 4 homolog isoform X6

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060941.1 Alternate T2T-CHM13v2.0

      Range
      82474164..82554047 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054316630.1 → XP_054172605.1  nuclear protein localization protein 4 homolog isoform X3

      UniProtKB/TrEMBL
      A0A994J7H4

    2. XM_054316629.1 → XP_054172604.1  nuclear protein localization protein 4 homolog isoform X2

      UniProtKB/TrEMBL
      A0A994J7H4

    3. XM_054316635.1 → XP_054172610.1  nuclear protein localization protein 4 homolog isoform X7

    4. XM_054316631.1 → XP_054172606.1  nuclear protein localization protein 4 homolog isoform X8

      UniProtKB/TrEMBL
      A0A994J7H4

    5. XM_054316632.1 → XP_054172607.1  nuclear protein localization protein 4 homolog isoform X4

      UniProtKB/TrEMBL
      A0A994J7H4

    6. XM_054316633.1 → XP_054172608.1  nuclear protein localization protein 4 homolog isoform X5

      UniProtKB/TrEMBL
      A0A994J7H4

    7. XM_054316628.1 → XP_054172603.1  nuclear protein localization protein 4 homolog isoform X1

      UniProtKB/TrEMBL
      A0A994J7H4

    8. XM_054316634.1 → XP_054172609.1  nuclear protein localization protein 4 homolog isoform X6

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8TAT6.3 GenPept UniProtKB/Swiss-Prot:Q8TAT6

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