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Tbio Signal peptide peptidase-like 3

Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries (PubMed:16873890, PubMed:25354954, PubMed:25827571). Acts like a sheddase by mediating the proteolytic release and secretion of active site-containing ectodomains of glycan-modifiying glycosidase and glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1 (PubMed:25354954, PubMed:25827571). Catalyzes the intramembrane cleavage of the envelope glycoprotein gp130 and/or the leader peptide gp18LP of the simian foamy virus independent of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852). May also have the ability to serve as a shedding protease for subsequent intramembrane proteolysis by SPPL2A and SPPL2B of the envelope glycoprotein gp130 (PubMed:23132852). Plays a role in the regulation of cellular glycosylation processes (PubMed:25354954). Required to link T-cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in lymphocytes by promoting the association of STIM1 and ORAI1 during store-operated calcium entry (SOCE) in a protease-independent manner (PubMed:25384971).

 Comments

Property Summary

NCBI Gene PubMed Count 19
PubMed Score 22.11
PubTator Score 12.11

Knowledge Summary

Patent

No data available

TINX Plot

  Disease (1)

Disease Target Count P-value
juvenile dermatomyositis 1189 1.6e-14
pituitary cancer 1972 4.6e-05
osteosarcoma 7933 1.6e-04
ovarian cancer 8491 1.0e-03

Expression

  Differential Expression (4)

Disease log2 FC p
osteosarcoma -1.140 1.6e-04
juvenile dermatomyositis 1.026 1.6e-14
ovarian cancer 1.200 1.0e-03
pituitary cancer 1.200 4.6e-05

Synonym

Accession Q8TCT6 Q3MJ04 Q8TAU4 Q96DD9 SPP-like 3
Symbols IMP2
PSH1
PSL4
PRO4332
MDHV1887

Gene

SPPL3

PANTHER Protein Class (3)

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG

 UniProt Keyword (10)

 GO Function (2)

 GO Component (9)

 GO Process (8)

 Compartment GO Term (57)

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 MGI Phenotype (3)

 GWAS Trait (1)

 HCA RNA Cell Line (56)

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Gene RIF (9)

PMID Text
25827571 Secretome analysis identifies novel signal Peptide peptidase-like 3 substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways
25827571 SPPL3 substrates identified on a proteome-wide scale in human and murine cells include numerous glycan-modifying enzymes residing in the Golgi network and implicated in distinct glycosylation pathways, including N-glycosylation, mucin-type O-glycosylation, O-mannosylation and glycosaminoglycan biosynthesis.
25384971 SPPL3 enhances the signal-induced association of stromal interaction molecule 1
25354954 Authors demonstrate that SPPL3 alters the pattern of cellular N-glycosylation by triggering the proteolytic release of active site-containing ectodomains of glycosidases and glycosyltransferases.
25354954 SPPL3 cleaves Golgi type II membrane proteins leading to their secretion. SPPL3 substrates include Golgi glycosyltransferases MGAT5, B4GALT1, and B3GNT1. By facilitating disengagement of these glycosyltransferases from their membrane anchors, SPPL3 causes their premature secretion and consequently orchestrates the extent of N-glycosylation on human and murine cells.
23132852 human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases.
16873890 SPPL3 cleaves a SPP substrate, but a more distantly related homologue SPPL2b does not, providing strong evidence that the malaria SPP and human SPPL3 have conserved active sites, while the active sites SPPL2b is distinct
15998642 SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER.
15385547 SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis

AA Sequence 

MAEQTYSWAYSLVDSSQVSTFLISILLIVYGSFRSLNMDFENQDKEKDSNSSSGSFNGEQEPIIGFQPMD      1 - 70
STRARFLPMGACVSLLVMFFFFDSVQVVFTICTAVLATIAFAFLLLPMCQYLTRPCSPQNKISFGCCGRF     71 - 140
TAAELLSFSLSVMLVLIWVLTGHWLLMDALAMGLCVAMIAFVRLPSLKVSCLLLSGLLIYDVFWVFFSAY    141 - 210
IFNSNVMVKVATQPADNPLDVLSRKLHLGPNVGRDVPRLSLPGKLVFPSSTGSHFSMLGIGDIVMPGLLL    211 - 280
CFVLRYDNYKKQASGDSCGAPGPANISGRMQKVSYFHCTLIGYFVGLLTATVASRIHRAAQPALLYLVPF    281 - 350
TLLPLLTMAYLKGDLRRMWSEPFHSKSSSSRFLEV                                       351 - 385
//

Text Mined References (20)

PMID Year Title
25827571 2015 Secretome analysis identifies novel signal Peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways.
25384971 2015 A protease-independent function for SPPL3 in NFAT activation.
25354954 2014 Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation.
23132852 2012 Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3).
20379614 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.
19197348 2009 Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.
17965014 2008 Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.
16873890 2006 Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase.
16829952 2006 SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
15998642 2005 Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3.
15489334 2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15385547 2004 Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins.
14702039 2004 Complete sequencing and characterization of 21,243 full-length human cDNAs.
12975309 2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.
12477932 2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.
12139484 2002 Novel class of polytopic proteins with domains associated with putative protease activity.
12077416 2002 Identification of signal peptide peptidase, a presenilin-type aspartic protease.
11978763 2002 Identification of a novel family of presenilin homologues.
8125298 1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.
2313285 1990 In vivo measurements of ethanol concentration in rabbit brain by 1H magnetic resonance spectroscopy.