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    SPPL2A signal peptide peptidase like 2A [ Homo sapiens (human) ]

    Gene ID: 84888, updated on 2-Nov-2024

    Summary

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    Official Symbol
    SPPL2Aprovided by HGNC
    Official Full Name
    signal peptide peptidase like 2Aprovided by HGNC
    Primary source
    HGNC:HGNC:30227
    See related
    Ensembl:ENSG00000138600 MIM:608238; AllianceGenome:HGNC:30227
    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
    IMP3; PSL2; IMD86
    Summary
    This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15. [provided by RefSeq, Feb 2012]
    Expression
    Ubiquitous expression in colon (RPKM 15.8), duodenum (RPKM 10.9) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See SPPL2A in Genome Data Viewer
    Location:
    15q21.2
    Exon count:
    16
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 15 NC_000015.10 (50702266..50765706, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 15 NC_060939.1 (48509322..48573674, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 15 NC_000015.9 (50994463..51057903, complement)

    Chromosome 15 - NC_000015.10Genomic Context describing neighboring genes Neighboring gene transient receptor potential cation channel subfamily M member 7 Neighboring gene uncharacterized LOC128092252 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr15:50969254-50969754 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr15:50969755-50970255 Neighboring gene H3K27ac hESC enhancer GRCh37_chr15:50978082-50978946 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6429 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 9397 Neighboring gene RNA, 7SL, cytoplasmic 354, pseudogene Neighboring gene MPRA-validated peak2334 silencer Neighboring gene HNF4 motif-containing MPRA enhancer 243 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6430 Neighboring gene Sharpr-MPRA regulatory region 3374 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr15:51104171-51104690 Neighboring gene ribosomal protein L32 pseudogene 30 Neighboring gene uncharacterized LOC124903490 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 9398

    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. Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. Schneppenheim J, et al. Biochem Biophys Res Commun, 2014 Aug 15. PMID 25035924, Free PMC Article
    2. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Kong XF, et al. Nat Immunol, 2018 Sep. PMID 30127434, Free PMC Article
    3. Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. Hüttl S, et al. Biochem J, 2016 May 15. PMID 26987812
    4. Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). Brady OA, et al. J Biol Chem, 2014 Jul 11. PMID 24872421, Free PMC Article
    5. 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

    See all (37) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis.
      Title: Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
    2. inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of dendritic cells and impairing IFN-gamma production by mycobacterium-specific memory TH1* cells
      Title: Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.
    3. Study propose that elements within the transmembrane segment and the luminal juxtamembrane domain facilitate intramembrane proteolysis of CD74 by SPPL2a.
      Title: Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.
    4. In human B cells, SPPL2a is indispensable for turnover of CD74 N-terminal fragment. A human 15q21.2 microdeletion leads to loss of SPPL2a transcript and protein.
      Title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
    5. Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
      Title: Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a).
    6. Data show that endogenous SPPL2a - in agreement with overexpression studies - is localised in membranes of lysosomes/late endosomes.
      Title: Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late endosomes by a tyrosine motif in its C-terminal tail.
    7. 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.
    8. ADAM10 and SPPL2a were identified as two proteases implicated in FasL processing and release of the FasL intracellular domain, which has been shown to be important for retrograde FasL signaling
      Title: The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
    9. 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.
    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

    Associated conditions

    Description Tests
    Immunodeficiency 86
    MedGen: C5561995 OMIM: 619549 GeneReviews: Not available
    		not available

    EBI GWAS Catalog

    Description
    Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
    EBI GWAS Catalog
    Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular 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)

    Genotypes

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables aspartic endopeptidase activity, intramembrane cleaving IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables aspartic endopeptidase activity, intramembrane cleaving IDA
    Inferred from Direct Assay
    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 immune response ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in regulation of tumor necrosis factor-mediated signaling pathway TAS
    Traceable Author Statement
    more info
    		  
    Component Evidence Code Pubs
    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 
    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 extracellular exosome HDA PubMed 
    located_in intracellular membrane-bounded organelle IDA
    Inferred from Direct Assay
    more info
    		  
    located_in late endosome IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in late endosome membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    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 
    located_in lysosomal membrane HDA PubMed 
    is_active_in lysosomal membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		  
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    signal peptide peptidase-like 2A
    Names
    IMP-3
    SPP-like 2A
    intramembrane cleaving protease
    intramembrane protease 3
    presenilin-like protein 2
    NP_116191.2
    XP_005254779.1
    XP_016878169.1
    XP_016878170.1
    XP_054234976.1
    XP_054234977.1
    XP_054234978.1
    XP_054234979.1

    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.

    mRNA and Protein(s)

    1. NM_032802.4 → NP_116191.2  signal peptide peptidase-like 2A precursor

      See identical proteins and their annotated locations for NP_116191.2

      Status: REVIEWED

      Source sequence(s)
      AA988423, AC012100, AK027446, AY169314
      Consensus CDS
      CCDS10138.1
      UniProtKB/Swiss-Prot
      B2RDS0, Q8TAW1, Q8TCT8, Q96SZ8
      UniProtKB/TrEMBL
      A0A8V8TN76
      Related
      ENSP00000261854.5, ENST00000261854.10
      Conserved Domains (2) summary
      cd02129
      Location:41 → 160
      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:210 → 496
      Peptidase_A22B; Signal peptide peptidase

    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_000015.10 Reference GRCh38.p14 Primary Assembly

      Range
      50702266..50765706 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_017022681.2 → XP_016878170.1  signal peptide peptidase-like 2A isoform X3

      UniProtKB/TrEMBL
      A0A8V8TLY7, A0A8V8TLZ2
      Related
      ENSP00000513581.1, ENST00000698135.1

    2. XM_017022680.2 → XP_016878169.1  signal peptide peptidase-like 2A isoform X2

      UniProtKB/TrEMBL
      A0A8V8TLY7

    3. XM_005254722.4 → XP_005254779.1  signal peptide peptidase-like 2A isoform X1

      UniProtKB/TrEMBL
      A0A8V8TN76
      Conserved Domains (2) summary
      cd02129
      Location:41 → 160
      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:210 → 514
      Peptidase_A22B; Signal peptide peptidase

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060939.1 Alternate T2T-CHM13v2.0

      Range
      48509322..48573674 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054379002.1 → XP_054234977.1  signal peptide peptidase-like 2A isoform X4

      UniProtKB/Swiss-Prot
      B2RDS0, Q8TAW1, Q8TCT8, Q96SZ8

    2. XM_054379001.1 → XP_054234976.1  signal peptide peptidase-like 2A isoform X1

    3. XM_054379004.1 → XP_054234979.1  signal peptide peptidase-like 2A isoform X3

      UniProtKB/TrEMBL
      A0A8V8TLZ2

    4. XM_054379003.1 → XP_054234978.1  signal peptide peptidase-like 2A isoform X2

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8TCT8.2 GenPept UniProtKB/Swiss-Prot:Q8TCT8

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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