SPOPL

Summary

SPOPL (speckle type BTB/POZ protein like, HGNC:27934) is a protein-coding gene on chromosome 2q22.1, encoding Speckle-type POZ protein-like (Q6IQ16). Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, but with relatively low efficiency.

Enables identical protein binding activity. Involved in negative regulation of protein ubiquitination and proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul3-RING ubiquitin ligase complex.

Source: NCBI Gene 339745 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 73 total
• MANE Select transcript: NM_001001664

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27934
Approved symbol	SPOPL
Name	speckle type BTB/POZ protein like
Location	2q22.1
Locus type	gene with protein product
Status	Approved
Aliases	BTBD33
Ensembl gene	ENSG00000144228
Ensembl biotype	protein_coding
Entrez	339745

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000280098, ENST00000420679, ENST00000430968, ENST00000449869, ENST00000458007, ENST00000467775, ENST00000881395, ENST00000881396, ENST00000881397

RefSeq mRNA: 1 — MANE Select: NM_001001664 NM_001001664

CCDS: CCDS33298

Canonical transcript exons

ENST00000280098 — 11 exons

Exon	Start	End
ENSE00000964116	138550483	138550604
ENSE00001160724	138550157	138550294
ENSE00001404196	138501770	138502119
ENSE00001419664	138568936	138573547
ENSE00002525246	138550903	138551054
ENSE00002526385	138552554	138552681
ENSE00003466246	138564708	138564850
ENSE00003500735	138560805	138560927
ENSE00003522783	138559282	138559337
ENSE00003667958	138564940	138564993
ENSE00003694110	138559022	138559199

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 94.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7510 / max 207.6864, expressed in 1653 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22729	5.1046	1590
22731	1.4119	691
22730	0.2344	92

Top tissues by expression

259 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	94.07	gold quality
germinal epithelium of ovary	UBERON:0001304	93.60	gold quality
tibia	UBERON:0000979	93.49	gold quality
visceral pleura	UBERON:0002401	92.98	gold quality
parietal pleura	UBERON:0002400	92.80	gold quality
calcaneal tendon	UBERON:0003701	92.66	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.57	gold quality
bronchial epithelial cell	CL:0002328	92.34	gold quality
skin of hip	UBERON:0001554	91.69	gold quality
monocyte	CL:0000576	91.67	gold quality
endothelial cell	CL:0000115	91.66	gold quality
tibialis anterior	UBERON:0001385	91.56	gold quality
bronchus	UBERON:0002185	91.56	gold quality
upper leg skin	UBERON:0004262	91.41	gold quality
cauda epididymis	UBERON:0004360	91.40	gold quality
leukocyte	CL:0000738	91.32	gold quality
ileal mucosa	UBERON:0000331	91.31	gold quality
deltoid	UBERON:0001476	91.06	gold quality
epithelium of mammary gland	UBERON:0003244	91.01	gold quality
mammary duct	UBERON:0001765	90.99	gold quality
trabecular bone tissue	UBERON:0002483	90.83	gold quality
palpebral conjunctiva	UBERON:0001812	90.72	gold quality
amniotic fluid	UBERON:0000173	90.16	gold quality
jejunal mucosa	UBERON:0000399	90.15	gold quality
eye	UBERON:0000970	90.07	gold quality
superficial temporal artery	UBERON:0001614	89.98	gold quality
parotid gland	UBERON:0001831	89.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.56	gold quality
substantia nigra pars compacta	UBERON:0001965	89.52	gold quality
thoracic mammary gland	UBERON:0005200	89.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.94
E-GEOD-100618	no	272.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

316 targeting SPOPL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588

Literature-anchored findings (GeneRIF, showing 2)

• Together, the data indicate that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and formation of multivesicular bodies by ubiquitinating and degrading EPS15 at endosomes. (PMID:27008177)
• SPOPL induces tumorigenicity and stemness in glioma stem cells by activating Notch signaling. (PMID:37523046)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spoplb	ENSDARG00000003974
danio_rerio	spopla	ENSDARG00000010563
mus_musculus	Spopl	ENSMUSG00000026771
rattus_norvegicus	Spopl	ENSRNOG00000005070
caenorhabditis_elegans		WBGENE00011815

Paralogs (11): BTBD1 (ENSG00000064726), ABTB1 (ENSG00000114626), SPOP (ENSG00000121067), KBTBD4 (ENSG00000123444), BTBD3 (ENSG00000132640), BTBD2 (ENSG00000133243), ABTB3 (ENSG00000151136), ABTB2 (ENSG00000166016), KLHL11 (ENSG00000178502), BTBD9 (ENSG00000183826), BTBD6 (ENSG00000184887)

Protein

Protein identifiers

Speckle-type POZ protein-like — Q6IQ16 (reviewed: Q6IQ16)

Alternative names: HIB homolog 2, Roadkill homolog 2

All UniProt accessions (3): Q6IQ16, F8WBB7, F8WD02

UniProt curated annotations — full annotation on UniProt →

Function. Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, but with relatively low efficiency. Cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL are less efficient than ubiquitin ligase complexes containing only SPOP. May function to down-regulate the activity of cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes that contain SPOP.

Subunit / interactions. Homodimer. Heterodimer with SPOP. Component of cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL. Interacts with CUL3 and MACROH2A1.

Subcellular location. Nucleus.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the Tdpoz family.

RefSeq proteins (1): NP_001001664* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR002083	MATH/TRAF_dom	Domain
IPR008974	TRAF-like	Homologous_superfamily
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily

Pfam: PF00651, PF22486

UniProt features (4 total): domain 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6IQ16-F1	86.49	0.68

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-162582	Signal Transduction
R-HSA-5358351	Signaling by Hedgehog

MSigDB gene sets: 200 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, ATGCAGT_MIR217, GTGCCTT_MIR506, CTAGGAA_MIR384, chr2q22, KOYAMA_SEMA3B_TARGETS_UP, WTGAAAT_UNKNOWN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, SENESE_HDAC1_TARGETS_UP

GO Biological Process (4): protein ubiquitination (GO:0016567), regulation of proteolysis (GO:0030162), negative regulation of protein ubiquitination (GO:0031397), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (3): ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
proteolysis	1
regulation of protein metabolic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
ubiquitin-like protein ligase binding	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

3081 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPOPL	CUL3	Q13618	982
SPOPL	NCOA3	Q9Y6Q9	563
SPOPL	NXPH2	O95156	473
SPOPL	RBX1	P62877	468
SPOPL	ESR1	P03372	451
SPOPL	SUFU	Q9UMX1	430
SPOPL	PSMB9	P28065	413
SPOPL	A0A1W2PRN6	A0A1W2PRN6	412
SPOPL	SPOP	O43791	409
SPOPL	CUL1	Q13616	374
SPOPL	EPS15	P42566	362
SPOPL	APMAP	Q9HDC9	356
SPOPL	PSMB8	P28062	351
SPOPL	FDXACB1	Q9BRP7	350
SPOPL	AR	P10275	349

IntAct

26 interactions, top by confidence:

A	B	Type	Score
NUP50	KPNA3	psi-mi:“MI:0914”(association)	0.780
SPOPL	KPNA5	psi-mi:“MI:0915”(physical association)	0.740
KPNA5	SPOPL	psi-mi:“MI:0915”(physical association)	0.740
SPOPL	SPOP	psi-mi:“MI:0407”(direct interaction)	0.590
SPOPL	SPOP	psi-mi:“MI:0914”(association)	0.590
CREB5	SPOPL	psi-mi:“MI:0915”(physical association)	0.560
SPOPL	MYD88	psi-mi:“MI:0915”(physical association)	0.560
ATF2	SPOPL	psi-mi:“MI:0915”(physical association)	0.560
RXRB	SPOPL	psi-mi:“MI:0915”(physical association)	0.560
SPOPL	SPOPL	psi-mi:“MI:0407”(direct interaction)	0.440
SPOPL	CUL3	psi-mi:“MI:0407”(direct interaction)	0.440
KPNA5	SPOP	psi-mi:“MI:0914”(association)	0.350
ATF2	SPOPL	psi-mi:“MI:0915”(physical association)	0.000
RXRB	SPOPL	psi-mi:“MI:0915”(physical association)	0.000
CREB5	SPOPL	psi-mi:“MI:0915”(physical association)	0.000
MYD88	SPOPL	psi-mi:“MI:0915”(physical association)	0.000
	SPOPL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): SPOPL (Two-hybrid), SPOPL (Affinity Capture-Western), SPOPL (Reconstituted Complex), EPS15 (Biochemical Activity), SPOPL (Two-hybrid), CREB5 (Two-hybrid), MYD88 (Two-hybrid), RXRB (Two-hybrid), SPOPL (Affinity Capture-MS), HOMER2 (Affinity Capture-MS), BBS5 (Affinity Capture-MS), HOMER1 (Affinity Capture-MS), GTF2IRD1 (Affinity Capture-MS), SPOP (Affinity Capture-MS), HOMER3 (Affinity Capture-MS)

ESM2 similar proteins: A0JMG1, A2VE52, D3K5L7, E0CZ16, E1C6Q1, E2R222, F1LZ52, F1LZF0, F1MBP6, O13016, O35345, O43791, O60684, O95164, O95198, O95544, P35815, P36993, P54797, P58058, P63143, P63144, Q0IHH9, Q0V7M0, Q0VCW1, Q15645, Q28528, Q28F89, Q2M2N2, Q2TA46, Q3UA06, Q4PJK1, Q5BL35, Q5NVK7, Q5RBV0, Q5REP9, Q5U1X1, Q5XHZ9, Q6GR09, Q6IQ16

Diamond homologs: A0JMG1, A1YEX3, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, B7U179, D3Z8N4, D4A2K4, E0CZ16, E7F6F9, F1LZF0, F1MBP6, O14682, O22286, O35709, O43791, O81432, O95198, P0DMR5, P0DMR6, P24278, P28575, P34568, P58544, P58545, Q08DK3, Q08DS0, Q0D2A9, Q0IHH9, Q0VCW1, Q16RL8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1914 predictions. Top by Δscore:

Variant	Effect	Δscore
2:138550156:GGTA:G	acceptor_gain	1.0000
2:138550156:GGTAA:G	acceptor_gain	1.0000
2:138550972:A:AG	acceptor_gain	1.0000
2:138550973:G:GA	acceptor_gain	1.0000
2:138550973:GTC:G	acceptor_gain	1.0000
2:138550973:GTCA:G	acceptor_gain	1.0000
2:138552552:A:AG	acceptor_gain	1.0000
2:138552553:G:GG	acceptor_gain	1.0000
2:138552553:GAAA:G	acceptor_gain	1.0000
2:138554437:A:AG	acceptor_gain	1.0000
2:138554438:G:GG	acceptor_gain	1.0000
2:138559275:GTTAC:G	acceptor_loss	1.0000
2:138559277:TACA:T	acceptor_loss	1.0000
2:138559278:ACAG:A	acceptor_loss	1.0000
2:138559279:CAGC:C	acceptor_loss	1.0000
2:138559280:A:AG	acceptor_gain	1.0000
2:138559280:A:C	acceptor_loss	1.0000
2:138559280:AGCTC:A	acceptor_gain	1.0000
2:138559281:G:GA	acceptor_gain	1.0000
2:138559281:GCT:G	acceptor_gain	1.0000
2:138559281:GCTC:G	acceptor_gain	1.0000
2:138559281:GCTCG:G	acceptor_gain	1.0000
2:138559333:AAAAG:A	donor_loss	1.0000
2:138559334:AAAGG:A	donor_loss	1.0000
2:138559336:AGGT:A	donor_loss	1.0000
2:138559338:G:GC	donor_loss	1.0000
2:138559339:T:A	donor_loss	1.0000
2:138560789:T:A	acceptor_gain	1.0000
2:138560796:C:CA	acceptor_gain	1.0000
2:138560800:A:AG	acceptor_gain	1.0000

AlphaMissense

2617 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:138550510:T:A	W36R	1.000
2:138550510:T:C	W36R	1.000
2:138550511:G:C	W36S	1.000
2:138550512:G:C	W36C	1.000
2:138550512:G:T	W36C	1.000
2:138550517:T:A	I38N	1.000
2:138550517:T:G	I38S	1.000
2:138550525:T:C	F41L	1.000
2:138550526:T:C	F41S	1.000
2:138550527:C:A	F41L	1.000
2:138550527:C:G	F41L	1.000
2:138550549:G:C	G49R	1.000
2:138550564:A:C	S54R	1.000
2:138550566:T:A	S54R	1.000
2:138550566:T:G	S54R	1.000
2:138550573:T:C	F57L	1.000
2:138550574:T:C	F57S	1.000
2:138550575:T:A	F57L	1.000
2:138550575:T:G	F57L	1.000
2:138550603:T:A	W67R	1.000
2:138550603:T:C	W67R	1.000
2:138550604:G:C	W67S	1.000
2:138550903:G:C	W67C	1.000
2:138550903:G:T	W67C	1.000
2:138550908:T:A	L69Q	1.000
2:138550908:T:C	L69P	1.000
2:138550911:G:C	R70T	1.000
2:138550911:G:T	R70M	1.000
2:138550912:G:C	R70S	1.000
2:138550912:G:T	R70S	1.000

dbSNP variants (sampled 300 via entrez): RS1000048908 (2:138505146 T>C), RS1000103575 (2:138532540 C>T), RS1000147577 (2:138526549 A>G), RS1000201616 (2:138526814 C>T), RS1000225915 (2:138555230 GGTT>G), RS1000227031 (2:138540054 G>A), RS1000256917 (2:138554991 C>T), RS1000300472 (2:138516379 G>A,T), RS1000304784 (2:138543410 A>G), RS1000310097 (2:138571555 G>A,T), RS1000321905 (2:138558234 T>G), RS1000410184 (2:138571068 AG>A), RS1000420861 (2:138510055 G>A), RS1000489613 (2:138564683 A>G), RS1000519598 (2:138525711 G>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001773_6	Response to antipsychotic treatment	1.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10170310	Efficacy	3	olanzapine	Schizophrenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10170310	SPOPL	3	0.00	1	olanzapine

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Plant Extracts	increases expression, affects cotreatment	1
Rotenone	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	increases expression	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.