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

Gene ID: 84888, updated on 11-Apr-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
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Genomic context

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Location:
15q21.2
Exon count:
16
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 15 NC_000015.10 (50702266..50765706, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 15 NC_060939.1 (48509322..48573674, complement)
105.20220307 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
  • 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. 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
  2. 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
  3. 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
  4. 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
  5. 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

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_2023_10

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

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