SPPL2B

Summary

SPPL2B (signal peptide peptidase like 2B, HGNC:30627) is a protein-coding gene on chromosome 19p13.3, encoding Signal peptide peptidase-like 2B (Q8TCT7). Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane.

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.

Source: NCBI Gene 56928 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 25 total
• GTEx eGene: eQTL in 41 tissues, sQTL in 12 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.11 (unconstrained)
• MANE Select transcript: NM_152988

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30627
Approved symbol	SPPL2B
Name	signal peptide peptidase like 2B
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	IMP4, PSL1, KIAA1532
Ensembl gene	ENSG00000005206
Ensembl biotype	protein_coding
OMIM	608239
Entrez	56928

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 22 protein_coding, 16 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000613503

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 3: 4, TSL 4: 1, TSL 5: 3

ENST00000613503, ENST00000585725, ENST00000586111, ENST00000586332, ENST00000587851, ENST00000589515, ENST00000593243, ENST00000610743, ENST00000612623, ENST00000614784, ENST00000614794, ENST00000618220, ENST00000621568, ENST00000622308, ENST00000894061, ENST00000894062, ENST00000894063, ENST00000894064, ENST00000894065, ENST00000894066, ENST00000894067, ENST00000894068, ENST00000894069, ENST00000957274, ENST00000957275, ENST00000957276, ENST00001006612, ENST00001006613, ENST00001006614, ENST00001006615, ENST00001006616, ENST00001026027, ENST00001026028, ENST00001026030, ENST00001026031, ENST00001026032, ENST00001026035, ENST00001026036, ENST00001026037, ENST00001026038, ENST00001059830, ENST00001059831, ENST00001059832, ENST00001059833, ENST00001138457

RefSeq mRNA: 2 — MANE Select: NM_152988 NM_001077238, NM_152988

CCDS: CCDS74252, CCDS74253

Canonical transcript exons

ENST00000613503 — 15 exons

Exon	Start	End
ENSE00003660174	2334602	2334721
ENSE00003706527	2352946	2355095
ENSE00003718751	2351434	2351594
ENSE00003722670	2340076	2340172
ENSE00003724298	2343965	2344039
ENSE00003728911	2339069	2339208
ENSE00003730643	2339824	2339966
ENSE00003731215	2328684	2328775
ENSE00003731485	2345253	2345330
ENSE00003733094	2337443	2337625
ENSE00003735866	2340898	2341014
ENSE00003739019	2344362	2344424
ENSE00003742937	2343211	2343292
ENSE00003751702	2338752	2338841
ENSE00003752424	2344553	2344652

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 98.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 508.3604 / max 4235.6408, expressed in 1828 samples.

Highest expression (Bgee): uterine tube, adenohypophysis, testis, hemisphere of cerebellum, small intestine Peyer’s patch.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPPL2B is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 12 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 53 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	1.7e-36	-0.26	19:2353370:G:A
Skin Not Sun Exposed Suprapubic	eqtl	3.1e-33	-0.27	19:2350116:C:T
Artery Tibial	eqtl	1.2e-28	-0.22	19:2345597:G:C
Brain Cortex	sqtl	1.8e-27	-1.79	19:2344036:C:A
Cells Cultured fibroblasts	eqtl	9.7e-27	-0.27	19:2345597:G:C
Adipose Subcutaneous	eqtl	2.3e-25	-0.26	19:2345597:G:C
Esophagus Mucosa	eqtl	2.6e-25	-0.23	19:2345597:G:C
Adipose Visceral Omentum	eqtl	1.4e-24	-0.26	19:2345597:G:C
Esophagus Muscularis	eqtl	9.2e-23	-0.19	19:2340237:C:T
Thyroid	eqtl	4.8e-22	-0.16	19:2346442:G:A
Esophagus Gastroesophageal Junction	eqtl	1.9e-20	-0.20	19:2356279:A:G
Pancreas	eqtl	8.1e-18	-0.34	19:2345597:G:C
Nerve Tibial	eqtl	1.6e-17	-0.16	19:2341104:AG:A
Brain Caudate basal ganglia	sqtl	8.1e-15	-1.50	19:2344036:C:A
Artery Aorta	eqtl	1.1e-14	-0.25	19:2345597:G:C
Lung	eqtl	8.0e-13	-0.16	19:2340237:C:T
Heart Atrial Appendage	eqtl	1.8e-12	-0.20	19:2340047:C:T
Testis	eqtl	1.4e-11	+0.21	19:2364192:G:GTGAA
Breast Mammary Tissue	eqtl	4.7e-11	-0.17	19:2340237:C:T
Heart Left Ventricle	eqtl	9.3e-11	-0.16	19:2341095:CCTCCCTGG:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
173068	481.1759	1828
173086	26.6703	1805
173085	0.5142	260

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.91	gold quality
adenohypophysis	UBERON:0002196	97.81	gold quality
left testis	UBERON:0004533	97.76	gold quality
right testis	UBERON:0004534	97.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.69	gold quality
metanephros cortex	UBERON:0010533	97.34	gold quality
transverse colon	UBERON:0001157	97.28	gold quality
cerebellar hemisphere	UBERON:0002245	97.23	gold quality
right lobe of thyroid gland	UBERON:0001119	97.14	gold quality
body of pancreas	UBERON:0001150	97.01	gold quality
left lobe of thyroid gland	UBERON:0001120	96.98	gold quality
mucosa of transverse colon	UBERON:0004991	96.95	gold quality
cerebellar cortex	UBERON:0002129	96.91	gold quality
body of stomach	UBERON:0001161	96.59	gold quality
pituitary gland	UBERON:0000007	95.90	gold quality
mucosa of stomach	UBERON:0001199	95.78	gold quality
left uterine tube	UBERON:0001303	95.69	gold quality
right ovary	UBERON:0002118	95.53	gold quality
minor salivary gland	UBERON:0001830	95.45	gold quality
left ovary	UBERON:0002119	95.38	gold quality
tibial nerve	UBERON:0001323	95.29	gold quality
granulocyte	CL:0000094	95.26	gold quality
skin of abdomen	UBERON:0001416	95.25	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.23	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.19	gold quality
small intestine	UBERON:0002108	95.16	gold quality
endocervix	UBERON:0000458	95.12	gold quality
skin of leg	UBERON:0001511	95.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.03	gold quality
body of uterus	UBERON:0009853	95.03	gold quality
right frontal lobe	UBERON:0002810	94.89	gold quality
thyroid gland	UBERON:0002046	94.79	gold quality
apex of heart	UBERON:0002098	94.54	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.31	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.29	gold quality
lower esophagus	UBERON:0013473	94.28	gold quality
right lobe of liver	UBERON:0001114	94.27	gold quality
spleen	UBERON:0002106	94.27	gold quality
ectocervix	UBERON:0012249	94.01	gold quality
right adrenal gland cortex	UBERON:0035827	94.00	gold quality
right adrenal gland	UBERON:0001233	93.97	gold quality
cerebellum	UBERON:0002037	93.97	gold quality
testis	UBERON:0000473	93.94	gold quality
stromal cell of endometrium	CL:0002255	93.89	gold quality
left adrenal gland cortex	UBERON:0035825	93.85	gold quality
left adrenal gland	UBERON:0001234	93.65	gold quality
lower esophagus mucosa	UBERON:0035834	93.50	gold quality
upper lobe of left lung	UBERON:0008952	93.47	gold quality
stomach	UBERON:0000945	93.32	gold quality
esophagus	UBERON:0001043	93.04	gold quality
right atrium auricular region	UBERON:0006631	93.03	gold quality
mouth mucosa	UBERON:0003729	92.98	gold quality
sural nerve	UBERON:0015488	92.97	gold quality
right lung	UBERON:0002167	92.96	gold quality
omental fat pad	UBERON:0010414	92.84	gold quality
left coronary artery	UBERON:0001626	92.78	gold quality
peritoneum	UBERON:0002358	92.78	gold quality
esophagus mucosa	UBERON:0002469	92.62	gold quality
right coronary artery	UBERON:0001625	92.56	gold quality
gastrocnemius	UBERON:0001388	92.33	gold quality
adrenal cortex	UBERON:0001235	92.22	gold quality
spinal cord	UBERON:0002240	92.17	gold quality
ventricular zone	UBERON:0003053	92.13	gold quality
saliva-secreting gland	UBERON:0001044	92.09	gold quality
ascending aorta	UBERON:0001496	92.09	gold quality
thoracic aorta	UBERON:0001515	92.04	gold quality
colon	UBERON:0001155	91.92	gold quality
coronary artery	UBERON:0001621	91.80	gold quality
tibial artery	UBERON:0007610	91.80	gold quality
popliteal artery	UBERON:0002250	91.79	gold quality
intestine	UBERON:0000160	91.78	gold quality
aorta	UBERON:0000947	91.76	gold quality
descending thoracic aorta	UBERON:0002345	91.74	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.54	gold quality
nucleus accumbens	UBERON:0001882	91.53	gold quality
sigmoid colon	UBERON:0001159	91.38	gold quality
upper lobe of lung	UBERON:0008948	91.26	gold quality
muscle of leg	UBERON:0001383	91.25	gold quality
large intestine	UBERON:0000059	91.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.12	gold quality
amygdala	UBERON:0001876	91.08	gold quality
adrenal gland	UBERON:0002369	90.92	gold quality
cingulate cortex	UBERON:0003027	90.89	gold quality
anterior cingulate cortex	UBERON:0009835	90.82	gold quality
zone of skin	UBERON:0000014	90.81	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.47	gold quality
caudate nucleus	UBERON:0001873	90.41	gold quality
fundus of stomach	UBERON:0001160	90.20	gold quality
gall bladder	UBERON:0002110	90.18	gold quality
lymph node	UBERON:0000029	90.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.97	gold quality
putamen	UBERON:0001874	89.81	gold quality
heart left ventricle	UBERON:0002084	89.72	gold quality
ovary	UBERON:0000992	89.25	gold quality
vagina	UBERON:0000996	89.08	gold quality
cardiac ventricle	UBERON:0002082	88.98	gold quality
cardiac atrium	UBERON:0002081	88.93	gold quality
ganglionic eminence	UBERON:0004023	88.81	gold quality
colonic epithelium	UBERON:0000397	88.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.83

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	58.5
Choroid plexus	tissue	40.5
Duodenum	tissue	39.1	medium
Small intestine	tissue	33.9	medium
Pancreas	tissue	28.1	high
Stomach 1	tissue	27.9	medium
Locus coeruleus	tissue	27.5
Bone marrow	tissue	27.3	high
Hippocampus	tissue	27.2	high
Testis	tissue	23.8	medium
Nucleus accumbens	tissue	23.6
Postcentral gyrus	tissue	22.4
Salivary gland	tissue	21.6	medium
Lymph node	tissue	19.3	medium
Vagina	tissue	19.3	low
Colon	tissue	18.6	medium
Skin 1	tissue	18.4	low
Spleen	tissue	18.2	high
Frontal cortex	tissue	16.2
Appendix	tissue	15.8	medium
Caudate putamen	tissue	14.8
Skeletal muscle	tissue	14.7	medium
Adipose tissue	tissue	12.6	not detected
Thymus	tissue	11.2
Fallopian tube	tissue	10.8	not detected
Cerebellum	tissue	10.7	medium
Parathyroid gland	tissue	10.3	low
Prostate	tissue	10.1	high
Gallbladder	tissue	10.0	high
Endometrium 1	tissue	9.9	not detected
Placenta	tissue	9.8	high
Adrenal gland	tissue	9.7	high
Superior colliculi	tissue	9.6
Tonsil	tissue	9.3	medium
Seminal vesicle	tissue	9.2	low
Periaqueductal gray	tissue	8.9
Spinal cord	tissue	8.8
Corpus callosum	tissue	8.8
Midbrain	tissue	8.7
Thalamus	tissue	8.7
Rectum	tissue	8.6	high
Medulla oblongata	tissue	8.6
Cerebral cortex	tissue	8.3	high
Somatosensory cortex	tissue	8.3
Pons	tissue	8.1
Lung	tissue	8.1	medium
Kidney	tissue	8.0	high
Heart muscle	tissue	7.8	medium
Occipital cortex	tissue	7.8
Ovary	tissue	7.7	not detected
Basal ganglia	tissue	7.5	high
Substantia nigra	tissue	7.5
Putamen	tissue	7.4
Hypothalamus	tissue	7.4
Esophagus	tissue	7.2	not detected
Hippocampal formation	tissue	7.2
Thyroid gland	tissue	6.9	high
Ventral forebrain	tissue	6.9
Retina	tissue	6.6
Motor cortex	tissue	6.6

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Nucleus ambiguus (44.4), Nucleus raphe pallidus (40.2), Nucleus cuneatus (39.0), Nucleus raphe obscurus (38.3), Ventral medullary reticular nucleus (37.8).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 2.86e-12, LOEUF 1.11, missense Z -1.34 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000613503 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 9)

• SPP, SPPL2a, -2b, -2c, and -3 probably cleave type II-oriented substrate peptides as shown by consensus analysis (PMID:15385547)
• SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER. (PMID:15998642)
• Results demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor alpha into the cytosol. (PMID:16829951)
• SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment. (PMID:17965014)
• Alzheimer disease-like mutant SPPL2b slowed intramembrane proteolysis of tumor necrosis factor alpha and caused a relative increase of longer intracellular cleavage products. (PMID:18768471)
• 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). (PMID:22194595)
• TfR1 N-terminal fragment is a substrate for intramembrane proteolysis by SPPL2b. (PMID:23384347)
• SPPL2a/b negatively regulates LOX-1 signaling and atherosclerosis. (PMID:30819724)
• Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Abeta-dependent expression in Alzheimer’s disease. (PMID:38367747)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sppl2	ENSDARG00000030448
mus_musculus	Sppl2b	ENSMUSG00000035206
rattus_norvegicus	Sppl2b	ENSRNOG00000057881

Paralogs (4): HM13 (ENSG00000101294), SPPL2A (ENSG00000138600), SPPL3 (ENSG00000157837), SPPL2C (ENSG00000185294)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1920468) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 3 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal retina vasculature morphology	1
decreased lean body mass	1
abnormal retina blood vessel morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Japonica Group	Q6ZGL9	97.1%	Diamond
Arabidopsis thaliana	O81062	80.9%	Diamond
Gallus gallus	Q5F383	79.4%	Diamond
Caenorhabditis elegans	P49049	45.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9UTA3	41.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PEAK3	protein-coding	374872
OAZ1	protein-coding	4946
LSM7	protein-coding	51690
LINGO3	protein-coding	645191
LINC01775	ncRNA	101928602
MIR7108	ncRNA	102466806
TIMM13	protein-coding	26517
TMPRSS9	protein-coding	360200
LMNB2	protein-coding	84823

Protein

Protein identifiers

Signal peptide peptidase-like 2B — Q8TCT7 (reviewed: Q8TCT7)

Alternative names: Intramembrane protease 4, Presenilin homologous protein 4, Presenilin-like protein 1

All UniProt accessions (5): Q8TCT7, A0A087WT77, A0A087WWL4, A0A087WZ50, A0A087WZ93

UniProt curated annotations — full annotation on UniProt →

Function. Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing. Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus. May play a role in the regulation of innate and adaptive immunity. Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis.

Subunit / interactions. Monomer. Homodimer. Interacts with ITM2B. Interacts with TNF. Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the leader peptide gp18LP.

Subcellular location. Cell membrane. Golgi apparatus membrane. Lysosome membrane. Endosome membrane. Membrane.

Tissue specificity. Expressed predominantly in adrenal cortex and mammary gland.

Post-translational modifications. Glycosylated.

Domain organisation. The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP.

Similarity. Belongs to the peptidase A22B family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TCT7-1	1	yes
Q8TCT7-2	2
Q8TCT7-4	4

RefSeq proteins (2): NP_001070706, NP_694533* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003137	PA_domain	Domain
IPR006639	Preselin/SPP	Family
IPR007369	Peptidase_A22B_SPP	Family
IPR046450	PA_dom_sf	Homologous_superfamily

Pfam: PF02225, PF04258

Enzyme classification (BRENDA)

• EC 3.4.23.B24 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (35 total): topological domain 10, transmembrane region 9, splice variant 3, compositionally biased region 2, active site 2, glycosylation site 2, signal peptide 1, chain 1, domain 1, region of interest 1, short sequence motif 1, sequence variant 1, mutagenesis site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TCT7-F1	76.62	0.32

Human Protein Atlas

Protein class: Enzymes, Peptidases, Aspartic-type peptidases, Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; plasma membrane; centrosome

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
359
421

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	97, 129

Mutagenesis-validated functional residues (1)

Position	Phenotype
421	loss of intramembrane-cleaving activity toward itm2b, tnf and the simian foamy virus envelope glycoprotein gp130.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-5357905	Regulation of TNFR1 signaling	curated
R-HSA-73887	Death Receptor Signaling	—
R-HSA-162582	Signal Transduction	—
R-HSA-75893	TNF signaling	—

MSigDB gene sets: 284 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MATURATION_OF_SSU_RRNA, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, TERAMOTO_OPN_TARGETS_CLUSTER_4, WEI_MYCN_TARGETS_WITH_E_BOX, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MARTINEZ_RB1_TARGETS_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (6): membrane protein ectodomain proteolysis (GO:0006509), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), membrane protein intracellular domain proteolysis (GO:0031293), membrane protein proteolysis (GO:0033619), regulation of immune response (GO:0050776), proteolysis (GO:0006508)

GO Molecular Function (5): aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (9): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), Golgi-associated vesicle membrane (GO:0030660), lumenal side of endoplasmic reticulum membrane (GO:0098553), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endosome (GO:0005768)

Reactome top-level categories

3 top-level categories:

Category	Pathways
TNF signaling	1
Signal Transduction	1
Death Receptor Signaling	1

GO top-level categories

30 GO namespaces:

Category	Terms
bounding membrane of organelle	3
membrane protein proteolysis	2
cytoplasmic vesicle membrane	2
endoplasmic reticulum membrane	2
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
proteolysis	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
protein metabolic process	1
aspartic-type endopeptidase activity	1
identical protein binding	1
protein dimerization activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
endosome	1
cellular anatomical structure	1
Golgi-associated vesicle	1
lumenal side of membrane	1
cytoplasmic side of membrane	1
endomembrane system	1
cytoplasmic vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
membrane protein ectodomain proteolysis	BP	direct assay
membrane protein intracellular domain proteolysis	BP	direct assay
membrane protein proteolysis	BP	direct assay
regulation of immune response	BP	mutant phenotype
Golgi-associated vesicle membrane	CC	direct assay
cytoplasmic side of endoplasmic reticulum membrane	CC	direct assay
endosome membrane	CC	direct assay
lumenal side of endoplasmic reticulum membrane	CC	direct assay
lysosomal membrane	CC	direct assay
membrane	CC	direct assay
plasma membrane	CC	direct assay
aspartic endopeptidase activity, intramembrane cleaving	MF	direct assay
protein homodimerization activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 828 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPPL2B	ITM2B	Q9Y287	576
SPPL2B	SPRYD4	Q8WW59	512
SPPL2B	ADAM10	O14672	464
SPPL2B	RCE1	Q9Y256	464
SPPL2B	TNF	P01375	464
SPPL2B	HM13	Q8TCT9	398
SPPL2B	SMCO3	A2RU48	391
SPPL2B	SHISA7	A6NL88	371
SPPL2B	SHISA6	Q6ZSJ9	365
SPPL2B	SPATA18	Q8TC71	364
SPPL2B	ODF1	Q14990	359
SPPL2B	ANKRD46	Q86W74	340
SPPL2B	PLCG1	P19174	334
SPPL2B	SYT13	Q7L8C5	333
SPPL2B	PSEN1	P49768	324

IntAct

Human interaction partners of SPPL2B in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
CD300E	association	0.530	1
UQCRQ	association	0.530	1
GPR89A	association	0.350	2
HAS3	association	0.350	1
POC1B-GALNT4	association	0.350	1

BioGRID (329 interactions; top human partners by supporting records): ENTPD7 (Affinity Capture-MS; 3 records), ERGIC3 (Affinity Capture-MS; 3 records), FAM187B (Affinity Capture-MS; 3 records), HTR3C (Affinity Capture-MS; 3 records), PON2 (Affinity Capture-MS; 3 records), PTCH1 (Affinity Capture-MS; 3 records), SLC8A3 (Affinity Capture-MS; 3 records), ABCB8 (Affinity Capture-MS; 2 records), ADIPOR1 (Affinity Capture-MS; 2 records), ALG10 (Affinity Capture-MS; 2 records), ATP1A3 (Affinity Capture-MS; 2 records), ATP1B4 (Affinity Capture-MS; 2 records), ATP9A (Affinity Capture-MS; 2 records), BRI3BP (Affinity Capture-MS; 2 records), CADM1 (Affinity Capture-MS; 2 records)

Disease & clinical

Genetic variants

Variant evidence for SPPL2B: 25 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

25 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	2
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 1,596):

Position(s)	Effect	Δscore	Sites
19:2334600–2334601	acceptor_loss	1.0000	3
19:2334722	donor_loss	1.0000	2
19:2338842–2338843	donor_loss	1.0000	5
19:2340173–2340174	donor_loss	1.0000	3
19:2340930	acceptor_gain	1.0000
19:2341015–2341016	donor_loss	1.0000	4
19:2343209–2343210	acceptor_loss	1.0000	4
19:2343293	donor_loss	1.0000	2
19:2328776–2328777	donor_loss	0.9900	5
19:2334600	acceptor_loss	0.9900	2

AlphaMissense

1,266 missense substitutions predicted likely pathogenic (of 3,815 scored), across 338 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M377	9	0.955	0.997
D359	8	0.996	0.999
D421	8	0.996	0.998
D436	8	0.986	0.997
F362	8	0.967	0.993
D172	8	0.957	0.980
F419	8	0.956	0.996
F255	8	0.953	0.996
F364	8	0.952	0.997
S375	8	0.948	0.997
F461	8	0.947	0.992
F179	8	0.904	0.977
F498	8	0.902	0.990
F229	8	0.893	0.974
F100	8	0.886	0.986
D147	8	0.839	0.925
F332	8	0.820	0.966
C98	7	0.992	0.996
C45	7	0.991	0.996
C410	7	0.990	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:608239 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST009325_95	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	4e-10
GCST002544_7	Parkinson’s disease	6e-7

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105912 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4069936	IC50	77 nM
CHEMBL4759048	IC50	1300 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.57	IC50	270	nM	CHEMBL4759048
6.37	IC50	430	nM	CHEMBL4069936

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(2S,3S)-3-amino-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propyl]-4-tert-butyl-N-cyclobutylbenzenesulfonamide	1673494: Inhibition of SPPL2b in human U2OS cells cotransfected with EGFP-labeled TNFalpha (1 to 76 residues)-NTF incubated for 24 hrs by Hoechst staining based Cellomics ArrayScan analysis	ic50	0.2700	uM
(2S)-2-cyclopropyl-N-[(6S)-5,11-dioxospiro[3,6-dihydro-1H-pyrazolo[1,2-b][2,3]benzodiazepine-2,1’-cyclopropane]-6-yl]-N’-(5-fluoro-2-methyl-3-pyridinyl)butanediamide	1479252: Inhibition of human SPPL2b expressed in human U2OS cells using EGFP-labeled TNFalpha (1 to 76 residues) NTF as substrate after 24 hrs by Hoechst staining based high content imaging assay	ic50	0.4300	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	3
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
MT19c compound	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Acrylamide	decreases expression	1
Magnetite Nanoparticles	decreases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4048267	Binding	Inhibition of human SPPL2b expressed in human U2OS cells using EGFP-labeled TNFalpha (1 to 76 residues) NTF as substrate after 24 hrs by Hoechst staining based high content imaging assay	Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo. — *J Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPPL2B across ~30M SureChEMBL compounds — explore on Sugi Predict.