SPSB4

Summary

SPSB4 (splA/ryanodine receptor domain and SOCS box containing 4, HGNC:30630) is a protein-coding gene on chromosome 3q23, encoding SPRY domain-containing SOCS box protein 4 (Q96A44). Substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including positive regulation of protein polyubiquitination; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol.

Source: NCBI Gene 92369 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_080862

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30630
Approved symbol	SPSB4
Name	splA/ryanodine receptor domain and SOCS box containing 4
Location	3q23
Locus type	gene with protein product
Status	Approved
Aliases	SSB-4
Ensembl gene	ENSG00000175093
Ensembl biotype	protein_coding
OMIM	611660
Entrez	92369

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000310546, ENST00000507895, ENST00000508126, ENST00000508828, ENST00000887577, ENST00000931037, ENST00000931038, ENST00000931039, ENST00000931040, ENST00000953715

RefSeq mRNA: 1 — MANE Select: NM_080862 NM_080862

CCDS: CCDS3115

Canonical transcript exons

ENST00000310546 — 3 exons

Exon	Start	End
ENSE00001205934	141051347	141051992
ENSE00001205942	141065952	141066798
ENSE00002063647	141147142	141148611

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 91.66.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6644 / max 59.3621, expressed in 241 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38864	0.5058	219
38865	0.0858	40
38867	0.0508	3
38866	0.0068	1
38869	0.0056	3
202949	0.0052	3
38868	0.0044	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.66	silver quality
cardiac muscle of right atrium	UBERON:0003379	89.47	gold quality
left ventricle myocardium	UBERON:0006566	88.95	gold quality
sperm	CL:0000019	85.65	gold quality
body of pancreas	UBERON:0001150	82.72	gold quality
ganglionic eminence	UBERON:0004023	82.12	gold quality
kidney epithelium	UBERON:0004819	81.90	gold quality
myocardium	UBERON:0002349	80.37	gold quality
ventricular zone	UBERON:0003053	80.24	gold quality
apex of heart	UBERON:0002098	78.94	gold quality
tendon of biceps brachii	UBERON:0008188	78.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.40	gold quality
cartilage tissue	UBERON:0002418	77.38	gold quality
cortical plate	UBERON:0005343	77.36	gold quality
epithelial cell of pancreas	CL:0000083	76.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.62	gold quality
left testis	UBERON:0004533	75.30	gold quality
nasal cavity epithelium	UBERON:0005384	75.17	gold quality
pancreas	UBERON:0001264	74.81	gold quality
testis	UBERON:0000473	74.68	gold quality
right testis	UBERON:0004534	74.58	gold quality
upper arm skin	UBERON:0004263	74.34	gold quality
heart left ventricle	UBERON:0002084	73.57	gold quality
cardiac ventricle	UBERON:0002082	73.40	gold quality
pituitary gland	UBERON:0000007	73.06	gold quality
vastus lateralis	UBERON:0001379	72.78	gold quality
quadriceps femoris	UBERON:0001377	71.98	gold quality
cerebellar vermis	UBERON:0004720	71.31	gold quality
vena cava	UBERON:0004087	71.21	gold quality
pancreatic ductal cell	CL:0002079	71.20	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

108 targeting SPSB4, 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-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641

Literature-anchored findings (GeneRIF, showing 1)

• Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbalpha ubiquitination and degradation and regulate circadian clock periodicity. (PMID:31607207)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spsb4b	ENSDARG00000040538
mus_musculus	Spsb4	ENSMUSG00000046997
rattus_norvegicus	Spsb4	ENSRNOG00000012862
drosophila_melanogaster	gus	FBGN0026238
caenorhabditis_elegans		WBGENE00021596
caenorhabditis_elegans		WBGENE00021597

Paralogs (4): SPSB2 (ENSG00000111671), SPSB3 (ENSG00000162032), SPSB1 (ENSG00000171621), FBXO45 (ENSG00000174013)

Protein

Protein identifiers

SPRY domain-containing SOCS box protein 4 — Q96A44 (reviewed: Q96A44)

All UniProt accessions (2): Q96A44, H0Y8T2

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Negatively regulates nitric oxide (NO) production and limits cellular toxicity in activated macrophages by mediating the ubiquitination and proteasomal degradation of NOS2. Acts as a bridge which links NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5. Diminishes EphB2-dependent cell repulsive responses by mediating the ubiquitination and degradation of EphB2/CTF2. Regulates cellular clock function by mediating the ubiquitin/proteasome-dependent degradation of the circadian transcriptional repressor NR1D1.

Subunit / interactions. Component of the probable ECS(SPSB4) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SPSB4. Interacts with CUL5; RNF7; ELOB and ELOC. Interacts with MET. Interacts (via B30.2/SPRY domain) with PAWR; this interaction occurs in association with the Elongin BC complex. Interacts with NOS2. Interacts with EPHB2.

Subcellular location. Cytoplasm. Cytosol.

Domain organisation. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes. Essential for its ability to link NOS2 and the ECS E3 ubiquitin ligase complex components ELOC and CUL5.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the SPSB family.

RefSeq proteins (1): NP_543138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001496	SOCS_box	Domain
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050672	FBXO45-Fsn/SPSB_families	Family

Pfam: PF00622, PF07525

UniProt features (27 total): strand 16, helix 3, turn 3, domain 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6DN7	X-RAY DIFFRACTION	1.4
6DN8	X-RAY DIFFRACTION	1.75
2V24	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96A44-F1	89.29	0.70

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 111 (showing top): GOBP_CIRCADIAN_RHYTHM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, TAATGTG_MIR323, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, AACTGGA_MIR145

GO Biological Process (7): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), intracellular signal transduction (GO:0035556), regulation of circadian rhythm (GO:0042752), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), rhythmic process (GO:0048511), positive regulation of protein polyubiquitination (GO:1902916)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of proteins	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
signal transduction	1
circadian rhythm	1
regulation of biological process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
biological_process	1
protein polyubiquitination	1
positive regulation of protein ubiquitination	1
regulation of protein polyubiquitination	1
enzyme-substrate adaptor activity	1
binding	1
cytoplasm	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

680 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPSB4	CISH	Q9NSE2	807
SPSB4	PAWR	Q96IZ0	507
SPSB4	C14orf119	Q9NWQ9	447
SPSB4	ASB6	Q9NWX5	444
SPSB4	MICAL3	Q7RTP6	441
SPSB4	SPSB3	Q6PJ21	422
SPSB4	CUL5	Q93034	414
SPSB4	TPPP	O94811	413
SPSB4	WDR93	Q6P2C0	401
SPSB4	PLAC9	Q5JTB6	397
SPSB4	SYN2	Q92777	396
SPSB4	LRRC41	Q15345	395
SPSB4	PYROXD1	Q8WU10	372
SPSB4	NWD2	Q9ULI1	358
SPSB4	JAKMIP3	Q5VZ66	358

IntAct

16 interactions, top by confidence:

A	B	Type	Score
SPSB4	ELOC	psi-mi:“MI:0915”(physical association)	0.670
SPSB4	ELOC	psi-mi:“MI:0914”(association)	0.670
CUL5	SOCS7	psi-mi:“MI:0914”(association)	0.640
PAWR	SPSB4	psi-mi:“MI:0407”(direct interaction)	0.590
VHL	SPSB4	psi-mi:“MI:0915”(physical association)	0.560
SLBP	ACAD11	psi-mi:“MI:0914”(association)	0.530
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
TMEM192	STXBP3	psi-mi:“MI:0914”(association)	0.530
SPSB4	vas	psi-mi:“MI:0407”(direct interaction)	0.440
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
SPSB4	BTAF1	psi-mi:“MI:0914”(association)	0.350
SFXN2	ROCK2	psi-mi:“MI:0914”(association)	0.350

BioGRID (145): SPSB4 (Affinity Capture-MS), CUL5 (Affinity Capture-MS), TCEB2 (Affinity Capture-MS), TCEB1 (Affinity Capture-MS), RNF7 (Affinity Capture-MS), EPHB2 (Affinity Capture-MS), Ephb2 (Affinity Capture-Western), EPHB2 (Affinity Capture-Western), SPSB4 (Affinity Capture-Western), NR1D1 (Affinity Capture-Western), SPSB4 (Affinity Capture-RNA), PCDH10 (Affinity Capture-MS), TAX1BP1 (Affinity Capture-MS), CDC16 (Affinity Capture-MS), KCTD3 (Affinity Capture-MS)

ESM2 similar proteins: A1Z6E0, A2BHJ4, A8IU92, B0X9V1, B3MDR0, B3NRP1, B4F739, B4GBN7, B4HQ29, B4J6Q0, B4KNC5, B4LMQ3, B4MR59, B4P4K8, B4QE02, P00860, P0C2W1, P0CH38, P11926, P27117, P27119, P27120, P48455, P53041, P53042, Q0G819, Q16XV7, Q290L5, Q5BJ41, Q5E9X6, Q5VST6, Q5XH73, Q60676, Q68FK8, Q6AXU9, Q6AY17, Q6IR85, Q6NZ03, Q7M759, Q7QGL9

Diamond homologs: A1Z6E0, A8QGZ7, A8XT88, B0X9V1, B3MDR0, B3NRP1, B4F739, B4GBN7, B4HQ29, B4J6Q0, B4KNC5, B4LMQ3, B4MR59, B4P4K8, B4QE02, O88838, P0C2W1, P0CH38, Q16XV7, Q18223, Q28DT9, Q290L5, Q5E9X6, Q5M877, Q6NZ03, Q7QGL9, Q7ZXY1, Q8K3B1, Q8R5B6, Q96A44, Q96BD6, Q99619, Q9D5L7, Q9V6L9, Q3ZBA7, Q8N3Y1, Q3MHZ2, Q571F5, Q6PJ21, Q3SX45

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

792 predictions. Top by Δscore:

Variant	Effect	Δscore
3:141147136:TTGCA:T	acceptor_loss	1.0000
3:141147137:TGCA:T	acceptor_loss	1.0000
3:141147138:GCAGC:G	acceptor_loss	1.0000
3:141147139:CAGCC:C	acceptor_loss	1.0000
3:141147140:A:AC	acceptor_loss	1.0000
3:141147140:A:AG	acceptor_gain	1.0000
3:141147140:AGCC:A	acceptor_gain	1.0000
3:141147141:G:GC	acceptor_gain	1.0000
3:141147141:GC:G	acceptor_gain	1.0000
3:141147141:GCC:G	acceptor_gain	1.0000
3:141147141:GCCG:G	acceptor_gain	1.0000
3:141147141:GCCGA:G	acceptor_gain	1.0000
3:141051989:TATG:T	donor_gain	0.9900
3:141051990:ATGG:A	donor_loss	0.9900
3:141051991:TG:T	donor_gain	0.9900
3:141051992:GG:G	donor_gain	0.9900
3:141051993:G:GA	donor_loss	0.9900
3:141051993:G:GG	donor_gain	0.9900
3:141065951:GGA:G	acceptor_gain	0.9900
3:141066799:G:GG	donor_gain	0.9900
3:141146340:G:T	donor_gain	0.9900
3:141051988:TTATG:T	donor_gain	0.9800
3:141051990:ATG:A	donor_gain	0.9800
3:141065946:TTCCA:T	acceptor_loss	0.9800
3:141065947:TCCA:T	acceptor_loss	0.9800
3:141065948:CCAG:C	acceptor_loss	0.9800
3:141065949:CAG:C	acceptor_loss	0.9800
3:141065950:A:AG	acceptor_gain	0.9800
3:141065950:A:AT	acceptor_loss	0.9800
3:141065950:AG:A	acceptor_gain	0.9800

AlphaMissense

1738 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:141066270:T:A	W56R	1.000
3:141066270:T:C	W56R	1.000
3:141066272:G:C	W56C	1.000
3:141066272:G:T	W56C	1.000
3:141066330:C:G	H76D	1.000
3:141066355:C:T	T84I	1.000
3:141066402:T:A	W100R	1.000
3:141066402:T:C	W100R	1.000
3:141066414:T:A	W104R	1.000
3:141066414:T:C	W104R	1.000
3:141066432:G:C	G110R	1.000
3:141066432:G:T	G110C	1.000
3:141066433:G:A	G110D	1.000
3:141066489:T:C	Y129H	1.000
3:141066490:A:G	Y129C	1.000
3:141066519:T:C	S139P	1.000
3:141066528:T:A	W142R	1.000
3:141066528:T:C	W142R	1.000
3:141066667:T:C	L188P	1.000
3:141066744:A:C	S214R	1.000
3:141066746:T:A	S214R	1.000
3:141066746:T:G	S214R	1.000
3:141066755:G:C	W217C	1.000
3:141066755:G:T	W217C	1.000
3:141066756:G:C	G218R	1.000
3:141066756:G:T	G218C	1.000
3:141066757:G:A	G218D	1.000
3:141066757:G:T	G218V	1.000
3:141066763:G:A	C220Y	1.000
3:141066764:T:G	C220W	1.000

dbSNP variants (sampled 300 via entrez): RS1000016357 (3:141076475 AG>A), RS1000062328 (3:141142517 C>T), RS1000063032 (3:141100691 G>T), RS1000104284 (3:141129121 C>A), RS1000118042 (3:141067279 C>T), RS1000119309 (3:141097867 A>T), RS1000166769 (3:141144141 T>A), RS1000191833 (3:141067582 G>A), RS1000192490 (3:141134855 C>G,T), RS1000223145 (3:141059192 G>A), RS1000232410 (3:141147768 T>C), RS1000235492 (3:141122784 C>G), RS1000239204 (3:141112600 C>G,T), RS1000250440 (3:141140611 G>A,T), RS1000302651 (3:141140742 T>C)

Disease associations

OMIM: gene MIM:611660 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001706_6	Stroke (ischemic)	6.000000e-07
GCST002286_2	Ischemic stroke	7.000000e-07
GCST003802_2	Response to citalopram or escitalopram in depression	3.000000e-07
GCST012311_23	Schizophrenia x sex interaction	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	5
trichostatin A	affects cotreatment, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
arsenite	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Arsenic	affects methylation	1
Vehicle Emissions	affects methylation, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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