FBXL8

Summary

FBXL8 (F-box and leucine rich repeat protein 8, HGNC:17875) is a protein-coding gene on chromosome 16q22.1, encoding F-box/LRR-repeat protein 8 (Q96CD0). Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. It shares 78% sequence identity with the mouse protein.

Source: NCBI Gene 55336 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_018378

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17875
Approved symbol	FBXL8
Name	F-box and leucine rich repeat protein 8
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Fbl8
Ensembl gene	ENSG00000135722
Ensembl biotype	protein_coding
OMIM	609077
Entrez	55336

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000258200, ENST00000517382, ENST00000518148, ENST00000518603, ENST00000519378, ENST00000519917, ENST00000519945, ENST00000521920, ENST00000523893, ENST00000959557

RefSeq mRNA: 1 — MANE Select: NM_018378 NM_018378

CCDS: CCDS10831

Canonical transcript exons

ENST00000258200 — 3 exons

Exon	Start	End
ENSE00000921129	67161735	67161937
ENSE00001206615	67162848	67164174
ENSE00002124981	67159957	67160056

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 92.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5671 / max 55.2450, expressed in 1641 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154577	6.0962	1622
154583	0.8140	182
154584	0.2482	81
154578	0.1415	69
154579	0.0812	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	92.15	gold quality
right uterine tube	UBERON:0001302	90.72	gold quality
prostate gland	UBERON:0002367	88.49	gold quality
minor salivary gland	UBERON:0001830	88.03	gold quality
left adrenal gland cortex	UBERON:0035825	87.98	gold quality
pituitary gland	UBERON:0000007	87.96	gold quality
right adrenal gland	UBERON:0001233	87.87	gold quality
saliva-secreting gland	UBERON:0001044	87.82	gold quality
skin of abdomen	UBERON:0001416	87.70	gold quality
left adrenal gland	UBERON:0001234	87.65	gold quality
right adrenal gland cortex	UBERON:0035827	87.35	gold quality
zone of skin	UBERON:0000014	86.89	gold quality
skin of leg	UBERON:0001511	86.49	gold quality
body of stomach	UBERON:0001161	86.35	gold quality
adenohypophysis	UBERON:0002196	86.05	gold quality
lower esophagus mucosa	UBERON:0035834	85.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.42	gold quality
fundus of stomach	UBERON:0001160	85.39	gold quality
adrenal gland	UBERON:0002369	85.03	gold quality
endocervix	UBERON:0000458	84.82	gold quality
right lobe of thyroid gland	UBERON:0001119	84.78	gold quality
right ovary	UBERON:0002118	84.69	gold quality
apex of heart	UBERON:0002098	84.26	gold quality
transverse colon	UBERON:0001157	84.25	gold quality
metanephros cortex	UBERON:0010533	84.12	gold quality
left lobe of thyroid gland	UBERON:0001120	84.08	gold quality
pancreas	UBERON:0001264	84.00	gold quality
cortex of kidney	UBERON:0001225	83.85	gold quality
mucosa of transverse colon	UBERON:0004991	83.76	gold quality
lower esophagus	UBERON:0013473	83.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting FBXL8, 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-6892-3P	99.68	66.40	1178
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4290	98.51	65.17	907

Literature-anchored findings (GeneRIF, showing 2)

• Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3. (PMID:33122824)
• SCF-FBXL8 contributes to liver metastasis and stem-cell-like features in colorectal cancer cells by mediating ubiquitination and degradation of TP53. (PMID:36855778)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxl8	ENSDARG00000054222
mus_musculus	Fbxl8	ENSMUSG00000033313
rattus_norvegicus	Fbxl8	ENSRNOG00000015242

Protein

Protein identifiers

F-box/LRR-repeat protein 8 — Q96CD0 (reviewed: Q96CD0)

Alternative names: F-box and leucine-rich repeat protein 8, F-box protein FBL8

All UniProt accessions (7): E5RFX2, E5RH15, E5RHS9, E5RIE9, E5RIS0, Q96CD0, J3QRE3

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Subunit / interactions. Directly interacts with SKP1 and CUL1.

RefSeq proteins (1): NP_060848* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily

Pfam: PF12937

UniProt features (3 total): chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96CD0-F1	91.78	0.78

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 96 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, BENPORATH_ES_WITH_H3K27ME3, chr16q22, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_SCF_UBIQUITIN_LIGASE_COMPLEX, GOCC_TRANSFERASE_COMPLEX, GOBP_PROTEOLYSIS, GOCC_CULLIN_RING_UBIQUITIN_LIGASE_COMPLEX

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

705 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXL8	SKP1	P34991	793
FBXL8	CUL1	Q13616	777
FBXL8	Q8WV35	Q8WV35	645
FBXL8	TMEM208	Q9BTX3	616
FBXL8	FBXL6	Q8N531	582
FBXL8	FBXL22	Q6P050	547
FBXL8	FBXL20	Q96IG2	503
FBXL8	FBXL2	Q9UKC9	478
FBXL8	ARFGEF1	Q9Y6D6	455
FBXL8	FBXL16	Q8N461	448
FBXL8	FBXL7	Q9UJT9	435
FBXL8	FBXO4	Q9UKT5	422
FBXL8	CACNA2D2	Q9NY47	420
FBXL8	KLHL18	O94889	418
FBXL8	MATCAP1	Q68EN5	417

IntAct

31 interactions, top by confidence:

A	B	Type	Score
SKP1	FBXL8	psi-mi:“MI:0915”(physical association)	0.930
FBXL8	SKP1	psi-mi:“MI:0915”(physical association)	0.930
SKP1	TTC9C	psi-mi:“MI:0914”(association)	0.870
SNAI1	KDM1A	psi-mi:“MI:0914”(association)	0.830
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
FBXL8	PICK1	psi-mi:“MI:0915”(physical association)	0.560
ALAS1	FBXL8	psi-mi:“MI:0915”(physical association)	0.560
FBXL8	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
ORC4	FBXL8	psi-mi:“MI:0915”(physical association)	0.370
Chmp6	NSF	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
SNAI1	EGR2	psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
SKP1	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
SKP1	NDC80	psi-mi:“MI:0914”(association)	0.350
SKP1	FBXL8	psi-mi:“MI:0915”(physical association)	0.000
FBXL8	PICK1	psi-mi:“MI:0915”(physical association)	0.000
FBXL8	SKP1	psi-mi:“MI:0915”(physical association)	0.000
FBXL8	ALAS1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): FBXL8 (Two-hybrid), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), FBXL8 (Two-hybrid), FBXL8 (Two-hybrid), FBXL8 (Two-hybrid), FBXL8 (Affinity Capture-MS), FBXL8 (Affinity Capture-MS), TP53 (Affinity Capture-Western), CUL1 (Affinity Capture-Western)

ESM2 similar proteins: A6NE02, A8MY62, C9JR72, D3Z7H8, D3ZU57, O09017, O15197, O19179, O95382, P0C0K6, P10588, P43136, P55203, Q02846, Q08DG4, Q15628, Q2KHV9, Q3U0S6, Q3UH93, Q5BK61, Q5U651, Q5W7P8, Q5ZMM1, Q6ZNJ1, Q6ZQA0, Q6ZVZ8, Q80ZD5, Q86WK7, Q8BH02, Q8BH83, Q8C828, Q8CIG9, Q8IUL8, Q8IYS2, Q8JGM4, Q8K2J9, Q8N239, Q8VHA6, Q91X21, Q96CD0

Diamond homologs: Q08DG4, Q8CIG9, Q96CD0, Q5BJ29, Q8N531, Q9QXW0, Q9UJT9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

453 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67161733:A:AG	acceptor_gain	1.0000
16:67161734:G:GG	acceptor_gain	1.0000
16:67161734:GGCC:G	acceptor_gain	1.0000
16:67161934:TCAGG:T	donor_loss	1.0000
16:67161935:CAGG:C	donor_loss	1.0000
16:67161936:AGGTG:A	donor_loss	1.0000
16:67161937:GGTG:G	donor_loss	1.0000
16:67161938:GT:G	donor_loss	1.0000
16:67161939:T:A	donor_loss	1.0000
16:67162834:G:A	acceptor_gain	1.0000
16:67162840:A:AG	acceptor_gain	1.0000
16:67160053:GCAG:G	donor_gain	0.9900
16:67160055:AG:A	donor_loss	0.9900
16:67160056:GG:G	donor_loss	0.9900
16:67161730:TCCAG:T	acceptor_loss	0.9900
16:67161731:CCA:C	acceptor_loss	0.9900
16:67161732:CA:C	acceptor_loss	0.9900
16:67161733:AGGCC:A	acceptor_gain	0.9900
16:67161734:GGCCG:G	acceptor_gain	0.9900
16:67161933:ATCAG:A	donor_gain	0.9900
16:67161934:TCAG:T	donor_gain	0.9900
16:67161938:G:GG	donor_gain	0.9900
16:67162832:A:AG	acceptor_gain	0.9900
16:67162832:ACG:A	acceptor_gain	0.9900
16:67162841:A:G	acceptor_gain	0.9900
16:67162846:A:G	acceptor_gain	0.9800
16:67160057:G:GG	donor_gain	0.9700
16:67161733:AG:A	acceptor_gain	0.9700
16:67161734:GG:G	acceptor_gain	0.9700
16:67162845:A:AG	acceptor_gain	0.9700

AlphaMissense

2354 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67163701:T:C	F336L	0.966
16:67163703:C:A	F336L	0.966
16:67163703:C:G	F336L	0.966
16:67163419:T:A	W242R	0.961
16:67163419:T:C	W242R	0.961
16:67163735:T:C	F347S	0.954
16:67163734:T:C	F347L	0.953
16:67163736:C:A	F347L	0.953
16:67163736:C:G	F347L	0.953
16:67163797:T:A	W368R	0.952
16:67163797:T:C	W368R	0.952
16:67163299:A:C	S202R	0.948
16:67163301:T:A	S202R	0.948
16:67163301:T:G	S202R	0.948
16:67163700:T:G	C335W	0.945
16:67163799:G:C	W368C	0.945
16:67163799:G:T	W368C	0.945
16:67161888:T:A	W35R	0.944
16:67161888:T:C	W35R	0.944
16:67163698:T:C	C335R	0.937
16:67161890:G:C	W35C	0.933
16:67161890:G:T	W35C	0.933
16:67163421:G:C	W242C	0.932
16:67163421:G:T	W242C	0.932
16:67163519:T:A	V275D	0.931
16:67161918:T:A	W45R	0.930
16:67161918:T:C	W45R	0.930
16:67163771:T:A	L359H	0.930
16:67163134:T:C	F147L	0.929
16:67163136:C:A	F147L	0.929

dbSNP variants (sampled 300 via entrez): RS1000740498 (16:67164070 C>G,T), RS1000879920 (16:67161279 A>G), RS1001112422 (16:67163042 T>A), RS1001230278 (16:67161479 G>A), RS1001913020 (16:67163634 G>A,T), RS1002182057 (16:67162226 G>A), RS1002389252 (16:67161889 G>A,C), RS1002829272 (16:67157982 G>T), RS1004361548 (16:67161959 C>G,T), RS1004466549 (16:67161238 C>G,T), RS1004696782 (16:67160604 G>A,T), RS1004727763 (16:67160953 T>G), RS1007004953 (16:67164570 T>A,C,G), RS1007245011 (16:67164266 G>A), RS1007643892 (16:67162736 G>A)

Disease associations

OMIM: gene MIM:609077 | disease phenotypes: MIM:116800

GenCC curated gene-disease

Mondo (1): cataract 5 multiple types (MONDO:0007290)

Orphanet (1): Early onset non-syndromic cataract (Orphanet:91492)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535342	Cataract, zonular (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
fluorene-9-bisphenol	decreases expression	1
bisphenol A	decreases methylation	1
methylselenic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Rotenone	decreases expression	1
Selenium	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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