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    SPPL2B signal peptide peptidase like 2B [ Homo sapiens (human) ]

    Gene ID: 56928, updated on 14-Nov-2024

    Summary

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    Official Symbol
    SPPL2Bprovided by HGNC
    Official Full Name
    signal peptide peptidase like 2Bprovided by HGNC
    Primary source
    HGNC:HGNC:30627
    See related
    Ensembl:ENSG00000005206 MIM:608239; AllianceGenome:HGNC:30627
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    IMP4; PSH4; PSL1; IMP-4
    Summary
    This gene encodes a member of the GXGD family of aspartic proteases. The GXGD proteases are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions. This enzyme localizes to endosomes, lysosomes, and the plasma membrane. It cleaves the transmembrane domain of tumor necrosis factor alpha to release the intracellular domain, which triggers cytokine expression in the innate and adaptive immunity pathways. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
    Expression
    Ubiquitous expression in testis (RPKM 13.2), duodenum (RPKM 10.9) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See SPPL2B in Genome Data Viewer
    Location:
    19p13.3
    Exon count:
    15
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 19 NC_000019.10 (2328684..2355095)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 19 NC_060943.1 (2302357..2328755)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 19 NC_000019.9 (2328683..2355093)

    Chromosome 19 - NC_000019.10Genomic Context describing neighboring genes Neighboring gene leucine rich repeat and Ig domain containing 3 Neighboring gene uncharacterized LOC101928572 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9785 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13676 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13677 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13678 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13679 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 9786 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13680 Neighboring gene H3K27ac hESC enhancer GRCh37_chr19:2328300-2328954 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13683 Neighboring gene LSM7 homolog, U6 small nuclear RNA and mRNA degradation associated Neighboring gene ReSE screen-validated silencer GRCh37_chr19:2358582-2358793 Neighboring gene transmembrane serine protease 9 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:2376438-2376950 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 13684 Neighboring gene uncharacterized LOC124904612 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:2426331-2427074 Neighboring gene origin of replication adjacent to lamin B2 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:2427075-2427820 Neighboring gene translocase of inner mitochondrial membrane 13

    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 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. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. Fluhrer R, et al. J Biol Chem, 2008 Oct 31. PMID 18768471, Free PMC Article
    2. A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b. Fluhrer R, et al. Nat Cell Biol, 2006 Aug. PMID 16829951
    3. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. Mentrup T, et al. J Exp Med, 2019 Apr 1. PMID 30819724, Free PMC Article
    4. Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease. Maccioni R, et al. Prog Neurobiol, 2024 Apr. PMID 38367747
    5. The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). Fluhrer R, et al. J Biol Chem, 2012 Feb 10. PMID 22194595, Free PMC Article

    See all (32) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Abeta-dependent expression in Alzheimer's disease.
      Title: Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease.
    2. SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis.
      Title: Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
    3. TfR1 N-terminal fragment is a substrate for intramembrane proteolysis by SPPL2b.
      Title: The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b.
    4. The alpha-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b).
      Title: The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b).
    5. Alzheimer disease-like mutant SPPL2b slowed intramembrane proteolysis of tumor necrosis factor alpha and caused a relative increase of longer intracellular cleavage products.
      Title: Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation.
    6. SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment.
      Title: Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
    7. SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER.
      Title: Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3.
    8. SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis
      Title: Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins.
    9. Results demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor alpha into the cytosol.
      Title: A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b.
    Submit: New GeneRIF Correction

    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
    Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
    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)

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ99014, KIAA1532, MGC111084

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables aspartic endopeptidase activity, intramembrane cleaving IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    NOT enables aspartic endopeptidase activity, intramembrane cleaving IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables aspartic endopeptidase activity, intramembrane cleaving IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables aspartic endopeptidase activity, intramembrane cleaving TAS
    Traceable Author Statement
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein homodimerization activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in membrane protein ectodomain proteolysis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in membrane protein intracellular domain proteolysis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in membrane protein intracellular domain proteolysis IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in membrane protein proteolysis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in membrane protein proteolysis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of immune response IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in regulation of tumor necrosis factor-mediated signaling pathway TAS
    Traceable Author Statement
    more info
    		  
    Component Evidence Code Pubs
    located_in Golgi membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    is_active_in Golgi-associated vesicle membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in Golgi-associated vesicle membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in actin cytoskeleton IDA
    Inferred from Direct Assay
    more info
    		  
    located_in centrosome IDA
    Inferred from Direct Assay
    more info
    		  
    is_active_in cytoplasmic side of endoplasmic reticulum membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in cytoplasmic side of endoplasmic reticulum membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in endosome membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    is_active_in lumenal side of endoplasmic reticulum membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in lumenal side of endoplasmic reticulum membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    is_active_in lysosomal membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in lysosomal membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    signal peptide peptidase-like 2B
    Names
    SPP-like 2B
    intramembrane protease 4
    presenilin homologous protein 4
    presenilin-like protein 1
    NP_001070706.1
    NP_694533.1
    XP_011526440.2
    XP_011526441.1
    XP_011526442.1
    XP_016882507.1
    XP_054177479.1
    XP_054177480.1
    XP_054177481.1
    XP_054177482.1

    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.

    Genomic

    1. NG_032984.1 RefSeqGene

      Range
      5055..31466
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001077238.2 → NP_001070706.1  signal peptide peptidase-like 2B isoform 3 precursor

      See identical proteins and their annotated locations for NP_001070706.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) uses an alternate splice site in the 3' coding region, compared to variant 2, resulting in an early stop codon. The encoded isoform (3) is shorter and has a distinct C-terminus compared to isoform 2.
      Source sequence(s)
      AB040965, BC028391, BC093046, BU733058
      Consensus CDS
      CCDS74253.1
      UniProtKB/Swiss-Prot
      Q8TCT7
      Related
      ENSP00000478510.1, ENST00000610743.4
      Conserved Domains (2) summary
      cd02129
      Location:44 → 163
      PA_hSPPL_like; PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the ...
      pfam04258
      Location:213 → 505
      Peptidase_A22B; Signal peptide peptidase

    2. NM_152988.3 → NP_694533.1  signal peptide peptidase-like 2B isoform 2 precursor

      See identical proteins and their annotated locations for NP_694533.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) represents the shorter transcript but encodes the longer isoform (2).
      Source sequence(s)
      AB040965, BC093046, BU733058
      Consensus CDS
      CCDS74252.1
      UniProtKB/Swiss-Prot
      D6W609, O60365, Q567S3, Q8IUH9, Q8TCT7, Q9BUY6, Q9H3M4, Q9NPN2, Q9P1Z6
      Related
      ENSP00000478298.1, ENST00000613503.5
      Conserved Domains (3) summary
      cd02129
      Location:44 → 163
      PA_hSPPL_like; PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the ...
      pfam04258
      Location:213 → 505
      Peptidase_A22B; Signal peptide peptidase
      cl25865
      Location:519 → 591
      Trypan_PARP; Procyclic acidic repetitive protein (PARP)

    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_000019.10 Reference GRCh38.p14 Primary Assembly

      Range
      2328684..2355095
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011528138.3 → XP_011526440.2  signal peptide peptidase-like 2B isoform X1

    2. XM_011528139.3 → XP_011526441.1  signal peptide peptidase-like 2B isoform X2

      Conserved Domains (1) summary
      pfam04258
      Location:82 → 374
      Peptidase_A22B; Signal peptide peptidase

    3. XM_017027018.3 → XP_016882507.1  signal peptide peptidase-like 2B isoform X3

    4. XM_011528140.2 → XP_011526442.1  signal peptide peptidase-like 2B isoform X4

      Conserved Domains (1) summary
      pfam04258
      Location:11 → 303
      Peptidase_A22B; Signal peptide peptidase

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060943.1 Alternate T2T-CHM13v2.0

      Range
      2302357..2328755
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054321504.1 → XP_054177479.1  signal peptide peptidase-like 2B isoform X1

    2. XM_054321505.1 → XP_054177480.1  signal peptide peptidase-like 2B isoform X2

    3. XM_054321506.1 → XP_054177481.1  signal peptide peptidase-like 2B isoform X3

    4. XM_054321507.1 → XP_054177482.1  signal peptide peptidase-like 2B isoform X4

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8TCT7.2 GenPept UniProtKB/Swiss-Prot:Q8TCT7

    Gene LinkOut

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