SPP2A_MOUSE
ID SPP2A_MOUSE Reviewed; 523 AA.
AC Q9JJF9; A2AI51; Q8R354;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Signal peptide peptidase-like 2A {ECO:0000250|UniProtKB:Q8TCT8};
DE Short=SPP-like 2A {ECO:0000250|UniProtKB:Q8TCT8};
DE Short=SPPL2a {ECO:0000250|UniProtKB:Q8TCT8};
DE EC=3.4.23.-;
DE AltName: Full=Intramembrane protease 3 {ECO:0000250|UniProtKB:Q8TCT8};
DE Short=IMP-3 {ECO:0000250|UniProtKB:Q8TCT8};
DE AltName: Full=Presenilin-like protein 2;
DE Flags: Precursor;
GN Name=Sppl2a {ECO:0000250|UniProtKB:Q8TCT8, ECO:0000312|MGI:MGI:1913802};
GN Synonyms=Imp3 {ECO:0000250|UniProtKB:Q8TCT8}, Psl2; ORFNames=MNCb-3763;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RA Osada N., Kusuda J., Tanuma R., Ito A., Hirata M., Sugano S., Hashimoto K.;
RT "Isolation of full-length cDNA clones from mouse brain cDNA library made by
RT oligo-capping method.";
RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-333.
RC TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP SUBCELLULAR LOCATION, TOPOLOGY, LYSOSOMAL TARGETING MOTIF, AND MUTAGENESIS
RP OF TYR-498 AND TYR-506.
RX PubMed=21896273; DOI=10.1016/j.febslet.2011.08.043;
RA Behnke J., Schneppenheim J., Koch-Nolte F., Haag F., Saftig P.,
RA Schroder B.;
RT "Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late
RT endosomes by a tyrosine motif in its C-terminal tail.";
RL FEBS Lett. 585:2951-2957(2011).
RN [6]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=30127434; DOI=10.1038/s41590-018-0178-z;
RA Kong X.F., Martinez-Barricarte R., Kennedy J., Mele F., Lazarov T.,
RA Deenick E.K., Ma C.S., Breton G., Lucero K.B., Langlais D., Bousfiha A.,
RA Aytekin C., Markle J., Trouillet C., Jabot-Hanin F., Arlehamn C.S.L.,
RA Rao G., Picard C., Lasseau T., Latorre D., Hambleton S., Deswarte C.,
RA Itan Y., Abarca K., Moraes-Vasconcelos D., Ailal F., Ikinciogullari A.,
RA Dogu F., Benhsaien I., Sette A., Abel L., Boisson-Dupuis S., Schroeder B.,
RA Nussenzweig M.C., Liu K., Geissmann F., Tangye S.G., Gros P., Sallusto F.,
RA Bustamante J., Casanova J.L.;
RT "Disruption of an antimycobacterial circuit between dendritic and helper T
RT cells in human SPPL2a deficiency.";
RL Nat. Immunol. 19:973-985(2018).
RN [7]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=33239420; DOI=10.4049/jimmunol.2000151;
RA Gradtke A.C., Mentrup T., Lehmann C.H.K., Cabrera-Cabrera F., Desel C.,
RA Okakpu D., Assmann M., Dalpke A., Schaible U.E., Dudziak D., Schroeder B.;
RT "Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial
RT Cytokine Responses of Dendritic Cells.";
RL J. Immunol. 206:164-180(2021).
CC -!- FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that
CC cleaves type II membrane signal peptides in the hydrophobic plane of
CC the membrane. Functions in FASLG, ITM2B and TNF processing. Catalyzes
CC the intramembrane cleavage of the anchored fragment of shed TNF-alpha
CC (TNF), which promotes the release of the intracellular domain (ICD) for
CC signaling to the nucleus. Also responsible for the intramembrane
CC cleavage of Fas antigen ligand FASLG, which promotes the release of the
CC intracellular FasL domain (FasL ICD). Essential for degradation of the
CC invariant chain CD74 that plays a central role in the function of
CC antigen-presenting cells in the immune system. Plays a role in the
CC regulation of innate and adaptive immunity.
CC {ECO:0000269|PubMed:30127434, ECO:0000269|PubMed:33239420}.
CC -!- SUBUNIT: Interacts with ITM2B. {ECO:0000250|UniProtKB:Q8TCT8}.
CC -!- SUBCELLULAR LOCATION: Late endosome membrane
CC {ECO:0000269|PubMed:21896273}; Multi-pass membrane protein
CC {ECO:0000305}. Lysosome membrane {ECO:0000269|PubMed:21896273}; Multi-
CC pass membrane protein {ECO:0000305}. Membrane
CC {ECO:0000250|UniProtKB:Q8TCT8}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8TCT8}; Lumenal side
CC {ECO:0000250|UniProtKB:Q8TCT8}. Note=Colocalizes with palmitoylated and
CC myristoylated proteins at the plasma membrane. {ECO:0000250}.
CC -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC The catalytic domains embedded in the membrane are in the opposite
CC orientation to that of the presenilin protein family; therefore, it is
CC predicted to cleave type II-oriented substrate peptides like the
CC prototypic protease SPP (By similarity). The C-terminal tail is
CC necessary for lysosomal transport (PubMed:21896273).
CC {ECO:0000250|UniProtKB:P49768, ECO:0000269|PubMed:21896273}.
CC -!- PTM: Glycosylated. {ECO:0000250|UniProtKB:P49768}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice increase susceptibility to
CC mycobacterial infection after BCG administration compared to wild-type
CC mice. Mutant animals have decreased numbers of DC2 dendritic cells
CC (cDC2), a smaller sized IFNG+ CD4+ and CD8+ T cell fraction, and
CC decreased production of IFNG by splenocytes compared to wild-type
CC animals. They also have profound B cell deficiency due to CD74 NTF
CC accumulation. The protein is required for optimal IFNG production by T
CC cells after mycobacterial infection (PubMed:30127434). Mutant mice
CC confirm depletion of conventional cDC2 cells in lymphatic tissues of
CC null mice. Detailed studies of bone marrow-derived dendritic cells
CC exposed to mycobacteria show enhanced secretion of Il1b, where
CC production of Il10 and Ifnb1 is reduced. There are also some
CC alterations in stimulation of pattern recognition receptors
CC (PubMed:33239420). {ECO:0000269|PubMed:30127434,
CC ECO:0000269|PubMed:33239420}.
CC -!- SIMILARITY: Belongs to the peptidase A22B family. {ECO:0000305}.
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DR EMBL; AB041547; BAA95032.1; -; mRNA.
DR EMBL; AL732330; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL928836; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466519; EDL28169.1; -; Genomic_DNA.
DR EMBL; BC026578; AAH26578.1; -; mRNA.
DR CCDS; CCDS16690.1; -.
DR RefSeq; NP_075709.2; NM_023220.2.
DR RefSeq; XP_011238039.1; XM_011239737.2.
DR AlphaFoldDB; Q9JJF9; -.
DR SMR; Q9JJF9; -.
DR BioGRID; 211552; 4.
DR IntAct; Q9JJF9; 2.
DR MINT; Q9JJF9; -.
DR STRING; 10090.ENSMUSP00000028844; -.
DR BindingDB; Q9JJF9; -.
DR ChEMBL; CHEMBL4105948; -.
DR MEROPS; A22.007; -.
DR TCDB; 1.A.54.3.1; the presenilin er ca(2+) leak channel (presenilin) family.
DR GlyGen; Q9JJF9; 6 sites.
DR iPTMnet; Q9JJF9; -.
DR PhosphoSitePlus; Q9JJF9; -.
DR SwissPalm; Q9JJF9; -.
DR EPD; Q9JJF9; -.
DR jPOST; Q9JJF9; -.
DR MaxQB; Q9JJF9; -.
DR PaxDb; Q9JJF9; -.
DR PeptideAtlas; Q9JJF9; -.
DR PRIDE; Q9JJF9; -.
DR ProteomicsDB; 258727; -.
DR Antibodypedia; 24774; 119 antibodies from 24 providers.
DR DNASU; 66552; -.
DR Ensembl; ENSMUST00000028844; ENSMUSP00000028844; ENSMUSG00000027366.
DR GeneID; 66552; -.
DR KEGG; mmu:66552; -.
DR UCSC; uc008mej.2; mouse.
DR CTD; 84888; -.
DR MGI; MGI:1913802; Sppl2a.
DR VEuPathDB; HostDB:ENSMUSG00000027366; -.
DR eggNOG; KOG2442; Eukaryota.
DR GeneTree; ENSGT00940000157722; -.
DR HOGENOM; CLU_023799_2_1_1; -.
DR InParanoid; Q9JJF9; -.
DR OMA; LSKDYCM; -.
DR OrthoDB; 535101at2759; -.
DR PhylomeDB; Q9JJF9; -.
DR TreeFam; TF319186; -.
DR BRENDA; 3.4.23.B24; 3474.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR BioGRID-ORCS; 66552; 0 hits in 74 CRISPR screens.
DR ChiTaRS; Sppl2a; mouse.
DR PRO; PR:Q9JJF9; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9JJF9; protein.
DR Bgee; ENSMUSG00000027366; Expressed in right colon and 265 other tissues.
DR ExpressionAtlas; Q9JJF9; baseline and differential.
DR Genevisible; Q9JJF9; MM.
DR GO; GO:0030660; C:Golgi-associated vesicle membrane; ISS:UniProtKB.
DR GO; GO:0071458; C:integral component of cytoplasmic side of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0071556; C:integral component of lumenal side of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005770; C:late endosome; ISO:MGI.
DR GO; GO:0031902; C:late endosome membrane; IDA:MGI.
DR GO; GO:0005765; C:lysosomal membrane; IDA:MGI.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; ISS:UniProtKB.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; ISS:UniProtKB.
DR GO; GO:0033619; P:membrane protein proteolysis; IMP:UniProtKB.
DR GO; GO:0050776; P:regulation of immune response; IMP:UniProtKB.
DR InterPro; IPR007369; Peptidase_A22B_SPP.
DR InterPro; IPR006639; Preselin/SPP.
DR PANTHER; PTHR12174; PTHR12174; 1.
DR Pfam; PF04258; Peptidase_A22B; 1.
DR SMART; SM00730; PSN; 1.
PE 1: Evidence at protein level;
KW Endosome; Glycoprotein; Hydrolase; Lysosome; Membrane; Protease;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..25
FT /evidence="ECO:0000250|UniProtKB:Q8TCT8"
FT CHAIN 26..523
FT /note="Signal peptide peptidase-like 2A"
FT /id="PRO_0000073911"
FT TOPO_DOM 26..175
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT8, ECO:0000255"
FT TRANSMEM 176..196
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 197..224
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 225..245
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 246..247
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 248..268
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 269..288
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 289..309
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 310..315
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 316..336
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 337..344
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 345..365
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 366..403
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT8"
FT TRANSMEM 404..424
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 425..440
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 441..461
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 462..463
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 464..484
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 485..523
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT8"
FT DOMAIN 70..155
FT /note="PA"
FT MOTIF 466..468
FT /note="PAL"
FT MOTIF 498..501
FT /note="YXXo lysosomal targeting motif"
FT ACT_SITE 355
FT /evidence="ECO:0000250|UniProtKB:P49810"
FT ACT_SITE 416
FT /evidence="ECO:0000250|UniProtKB:P49810"
FT CARBOHYD 51
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 61
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 69
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 119
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 129
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 135
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 498
FT /note="Y->A: Inhibits lysosomal/late endosomal targeting."
FT /evidence="ECO:0000269|PubMed:21896273"
FT MUTAGEN 506
FT /note="Y->A: Does not inhibit lysosomal/late endosomal
FT targeting."
FT /evidence="ECO:0000269|PubMed:21896273"
FT CONFLICT 74
FT /note="A -> P (in Ref. 2; AAH26578)"
FT /evidence="ECO:0000305"
FT CONFLICT 331..333
FT /note="NLI -> PKV (in Ref. 2; AAH26578)"
FT /evidence="ECO:0000305"
FT CONFLICT 502
FT /note="D -> G (in Ref. 1; BAA95032)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 523 AA; 58129 MW; A15109A71FCF25C4 CRC64;
MGLLHSLHAP AAALLWSCLL GLAAAQEAIL HASTNGVSSL SKDYCMYYNN NWTRLPSSLE
NATSLSLMNL TGTALCHLSD IPPDGIRNKA VVVHWGPCHF LEKARIAQEG GAAALLIANN
SVLIPSSRNK STFQNVTVLI AVITQKDFKD MKETLGDDIT VKMYSPSWPN FDYTLVVIFV
IAVFTVALGG YWSGLIELEN MKSVEDAEDR ETRKKKDDYL TFSPLTVVVF VVICCIMIVL
LYFFYRWLVY VMIAIFCIAS SMSLYNCLSA LIHRMPCGQC TILCCGKNIK VSLIFLSGLC
ISVAVVWAVF RNEDRWAWIL QDILGIAFCL NLIKTMKLPN FMSCVILLGL LLIYDVFFVF
ITPFITKNGE SIMVELAAGP FENAEKLPVV IRVPKLMGYS VMSVCSVPVS VLGFGDIIVP
GLLIAYCRRF DVQTGSSIYY ISSTIAYAVG MIITFVVLMV MKTGQPALLY LVPCTLITVS
VVAWSRKEMK KFWKGSSYQV MDHLDYSTNE ENPVTTDEQI VQQ
