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

Gene ID: 55666, updated on 11-Apr-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 ATPase binding activity; 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 cellular protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]
Expression
Ubiquitous expression in testis (RPKM 14.2), esophagus (RPKM 10.3) and 25 other tissues See more
Orthologs
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Genomic context

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Location:
17q25.3
Exon count:
21
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (81556885..81637112, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (82474164..82554047, complement)
105.20220307 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. 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
  2. Structural basis for the interaction between human Npl4 and Npl4-binding motif of human Ufd1. Nguyen TQ, et al. Structure, 2022 Nov 3. PMID 36087575
  3. Mechanistic insight into substrate processing and allosteric inhibition of human p97. Pan M, et al. Nat Struct Mol Biol, 2021 Jul. PMID 34262183
  4. 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
  5. Ufd1-Npl4 is a negative regulator of cholera toxin retrotranslocation. McConnell E, et al. Biochem Biophys Res Commun, 2007 Apr 20. PMID 17331469

See all (136) 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)

Genotypes

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 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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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_2023_10

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

  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

  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

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

  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

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

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

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

  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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