ALYREF

Summary

ALYREF (Aly/REF export factor, HGNC:19071) is a protein-coding gene on chromosome 17q25.3, encoding THO complex subunit 4 (Q86V81). Functions as an mRNA export adapter; component of the transcription/export (TREX) complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. It is a common-essential gene (DepMap: required in 98.1% of cancer cell lines).

The protein encoded by this gene is a heat stable, nuclear protein and functions as a molecular chaperone. It is thought to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins.

Source: NCBI Gene 10189 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 15 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_005782

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19071
Approved symbol	ALYREF
Name	Aly/REF export factor
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	ALY, BEF, ALY/REF, REF
Ensembl gene	ENSG00000183684
Ensembl biotype	protein_coding
OMIM	604171
Entrez	10189

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding_CDS_not_defined, 2 protein_coding, 1 retained_intron

ENST00000504015, ENST00000505490, ENST00000511412, ENST00000512673, ENST00000864755

RefSeq mRNA: 1 — MANE Select: NM_005782 NM_005782

CCDS: CCDS32768

Canonical transcript exons

ENST00000505490 — 6 exons

Exon	Start	End
ENSE00001294955	81888241	81888418
ENSE00001298141	81891323	81891586
ENSE00002022356	81887835	81888145
ENSE00003572266	81888520	81888583
ENSE00003601841	81889182	81889329
ENSE00003658206	81890689	81890820

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 97.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 157.8760 / max 838.8614, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168845	154.6004	1828
168846	2.9144	799
168847	0.3611	160

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.12	gold quality
ventricular zone	UBERON:0003053	96.87	gold quality
stromal cell of endometrium	CL:0002255	96.68	gold quality
left testis	UBERON:0004533	96.67	gold quality
mucosa of transverse colon	UBERON:0004991	96.64	gold quality
right testis	UBERON:0004534	96.55	gold quality
monocyte	CL:0000576	96.46	gold quality
leukocyte	CL:0000738	96.24	gold quality
granulocyte	CL:0000094	95.61	gold quality
vermiform appendix	UBERON:0001154	95.53	gold quality
skin of abdomen	UBERON:0001416	95.46	gold quality
bone marrow cell	CL:0002092	95.20	gold quality
tendon of biceps brachii	UBERON:0008188	95.15	gold quality
calcaneal tendon	UBERON:0003701	95.07	gold quality
skin of leg	UBERON:0001511	94.86	gold quality
esophagus mucosa	UBERON:0002469	94.84	gold quality
testis	UBERON:0000473	94.81	gold quality
left uterine tube	UBERON:0001303	94.71	gold quality
thymus	UBERON:0002370	94.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.06	gold quality
tendon	UBERON:0000043	93.97	gold quality
spleen	UBERON:0002106	93.88	gold quality
transverse colon	UBERON:0001157	93.65	gold quality
ectocervix	UBERON:0012249	93.60	gold quality
upper lobe of left lung	UBERON:0008952	93.53	gold quality
zone of skin	UBERON:0000014	93.52	gold quality
esophagus	UBERON:0001043	93.49	gold quality
omental fat pad	UBERON:0010414	93.35	gold quality
peritoneum	UBERON:0002358	93.32	gold quality
adenohypophysis	UBERON:0002196	93.26	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	234.34
E-HCAD-13	yes	174.05
E-ANND-3	yes	6.09
E-MTAB-6379	no	35.78
E-GEOD-124858	no	23.79

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

18 targeting ALYREF, 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-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-4733-5P	97.75	67.44	866

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 33)

• recruitment of the human TREX complex to spliced mRNA is not directly coupled to transcription, but is instead coupled to transcription indirectly through splicing (PMID:15998806)
• suggest a central role for ALY in T-cell enhancer function and oncogene activation (PMID:17229714)
• Increased TAP binding correlates with increased SF2/ASF binding, but not increased REF/Aly or Y14 binding. (PMID:18243119)
• Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. (PMID:18562279)
• Adaptor Aly functions in the Tap-p15-mediated nuclear export of HSP70 mRNA. (PMID:19165146)
• The authors demonstrate that ORF57 recruits several members of hTREX, namely Aly, UAP56 and hTHO-complex proteins, onto the viral mRNAs to assemble an export-competent ribonucleoprotein particle. (PMID:19264631)
• TAP/NXF1, but not Aly/REF, is required for RNA export during HSV-1 infection. (PMID:19369354)
• These results indicate that ICP27 RGG box methylation regulates interaction ALY and SRPK1 proteins. (PMID:19553338)
• Results describe the subcellular localization of ICP27 and its colocalization with cellular RNA export factors Aly/REF and TAP/NXF1. (PMID:20015986)
• When the TREX components UAP56 or Aly are knocked down, spliced mRNA, as well as total polyA+ RNA, accumulates in nuclear speckle domains. (PMID:20981025)
• A differential connection between tumorogenesis and the expression levels of human THO and ALY. (PMID:21329510)
• REF/Aly-ORF57 interaction is not essential for KSHV lytic replication but may contribute to target RNA stability independent of effects on RNA export, suggesting a novel role for REF/Aly in viral RNA metabolism. (PMID:22761374)
• Authors propose that Aly, THO and UAP56 form a highly integrated unit to associate with the spliced mRNA and function in mRNA export. (PMID:23222130)
• High ALY expression is associated with lymph node metastasis in oral squamous cell carcinoma. (PMID:23242234)
• ALY is a novel E2F2-interacting protein and a relevant modulator of E2F-responsive gene expression. (PMID:23297349)
• The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export. (PMID:23637401)
• a spatial map is produced in living cells of the sites for the interaction of two TREX subunits, Alyref and Chtop, with Nxf1. (PMID:23826332)
• the data provides the first site-specific description of how viral mRNA is locked by a herpes viral adaptor protein in complex with cellular ALYREF, giving herpesvirus access to the cellular mRNA export machinery (PMID:24550725)
• A short conserved motif in ALYREF directs cap- and exon junction complex-dependent assembly of export complexes on spliced mRNAs. (PMID:26773052)
• small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secretion. (PMID:27807029)
• Dysregulation of ALYREF-mediated mRNA export upon NSUN2 depletion could be restored by reconstitution of wild-type but not methyltransferase-defective NSUN2. (PMID:28418038)
• The competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. (PMID:28801509)
• ALYREF mainly binds to the 5’ and the 3’ regions of the mRNA. ALYREF is likely recruited to mRNAs by PABPN1 and the 3’ processing machinery. (PMID:28934468)
• In both ORF57 and ICP27 the interaction sites for ALYREF and UIF partially overlap, suggestive of mutually exclusive binding. The data provide a map of the binding sites responsible for promoting herpes virus mRNA export, enabling future studies to accurately probe these interactions and reveal the functional consequences for UIF and ALYREF redundancy (PMID:30301920)
• We demonstrate that eIF4A3 stimulates Alyref deposition not only on spliced RNAs close to exon junction complex sites but also on single-exon transcripts (PMID:31104896)
• An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability. (PMID:33767157)
• The role of the HIF-1alpha/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. (PMID:33991457)
• ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform. (PMID:35776213)
• m[5]C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. (PMID:36806253)
• ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. (PMID:38135116)
• Pan-cancer analysis of RNA 5-methylcytosine reader (ALYREF). (PMID:38361753)
• HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development. (PMID:38626369)
• ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA. (PMID:39117671)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Alyref	ENSMUSG00000025134
mus_musculus	Alyref2	ENSMUSG00000060244
mus_musculus	Alyreffm1	ENSMUSG00000086727
mus_musculus	Alyreffm10	ENSMUSG00000090854
mus_musculus	Alyreffm5	ENSMUSG00000091101
mus_musculus	Alyreffm11	ENSMUSG00000091779
mus_musculus	Alyreffm17	ENSMUSG00000094144
mus_musculus	Alyreffm2	ENSMUSG00000094215
mus_musculus	Alyreffm4	ENSMUSG00000094314
mus_musculus	Alyreffm15	ENSMUSG00000095022
mus_musculus	Alyreffm12	ENSMUSG00000095673
mus_musculus	Alyreffm9	ENSMUSG00000096640
mus_musculus	Alyreffm8	ENSMUSG00000096744
mus_musculus	Alyreffm14	ENSMUSG00000097427
mus_musculus	Alyreffm16	ENSMUSG00000097550
mus_musculus	Alyreffm13	ENSMUSG00000097878
mus_musculus	Alyreffm7	ENSMUSG00000112856
mus_musculus	Alyreffm6	ENSMUSG00000112931
mus_musculus	Alyreffm3	ENSMUSG00000117091
rattus_norvegicus	Alyref	ENSRNOG00000036687
caenorhabditis_elegans		WBGENE00000121
caenorhabditis_elegans		WBGENE00000122

Paralogs (2): POLDIP3 (ENSG00000100227), CHTOP (ENSG00000160679)

Protein

Protein identifiers

THO complex subunit 4 — Q86V81 (reviewed: Q86V81)

Alternative names: Ally of AML-1 and LEF-1, Aly/REF export factor, Transcriptional coactivator Aly/REF, bZIP-enhancing factor BEF

All UniProt accessions (1): E9PB61

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an mRNA export adapter; component of the transcription/export (TREX) complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5’ end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway. Involved in the nuclear export of intronless mRNA; proposed to be recruited to intronless mRNA by ATP-bound DDX39B. Plays a key role in mRNP recognition and mRNA packaging by bridging the mRNP-bound EJC and the TREX core complex. TREX recruitment occurs via an interaction between ALYREF/THOC4 and the cap-binding protein NCBP1. Required for TREX complex assembly and for linking DDX39B to the cap-binding complex (CBC). Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway). In conjunction with THOC5 functions in NXF1-NXT1 mediated nuclear export of HSP70 mRNA; both proteins enhance the RNA binding activity of NXF1 and are required for NXF1 localization to the nuclear rim. Involved in mRNA export of C5-methylcytosine (m5C)-containing mRNAs: specifically recognizes and binds m5C mRNAs and mediates their nucleo-cytoplasmic shuttling. Acts as a chaperone and promotes the dimerization of transcription factors containing basic leucine zipper (bZIP) domains and thereby promotes transcriptional activation. Involved in transcription elongation and genome stability. (Microbial infection) The TREX complex is essential for the export of Kaposi’s sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production; ALYREF/THOC4 mediates the recruitment of the TREX complex to the intronless viral mRNA.

Subunit / interactions. Homomultimer; predominantly hexamer when bound to EJC-RNA complex. Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex (THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7); in the complex interacts (via UAP56-binding motif) with DDX39B with low affinity but this interaction is likely stabilized by multimerization. TREX seems to have a dynamic structure involving ATP-dependent remodeling; in the complex interacts with THOC1, THOC2 and THOC5. Component of the ALYREF/THOC4-EJC-RNA complex; in the complex interacts (via the WXHD motif) with EIF4A3 and interacts (via the RRM domain) with MAGOH; these interactions are likely specific to RNA-bound EJC. Bridges the THO-DDX39B and EJC-RNA complexes to form the TREX-EJC-RNA complex; this interaction is essential for mRNP recognition and mRNA packaging. Identified in the spliceosome C complex. Found in a mRNP complex with UPF3A and UPF3B. Interacts with RBM8A, RBM15B, NCBP1, LEF1, RUNX1, RNPS1, SRRM1, IWS1 and EXOSC1. Interacts with RBM15B. Interacts with NXF1; the interaction is direct. Interacts with IVNS1ABP (via BACK domain); the interaction is indirect and likely plays a role in mRNA nuclear export. (Microbial infection) Interacts with human Kaposi’s sarcoma-associated herpesvirus (HHV-8) ORF57 protein; this interaction allows efficient export of HHV-8 early and late intronless transcripts. (Microbial infection) Interacts with HHV-1 ICP27 protein; this interaction recruits ALYREF to viral replication compartments and probably directs viral mRNA to the TAP/NXF1 pathway.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Expressed in a wide variety of cancer types.

Post-translational modifications. Arg-204 is dimethylated, probably to asymmetric dimethylarginine. Arginine methylation reduces RNA binding. Citrullinated by PADI4.

Miscellaneous. Antibodies against ALYREF/THOC4 are found in sera of patients with systemic lupus erythematosus (SLE).

Similarity. Belongs to the ALYREF family.

RefSeq proteins (1): NP_005773* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR025715	FoP_C	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR051229	ALYREF_mRNA_export	Family

Pfam: PF00076, PF13865

UniProt features (52 total): modified residue 18, region of interest 9, compositionally biased region 5, mutagenesis site 5, sequence conflict 5, strand 4, helix 2, initiator methionine 1, chain 1, short sequence motif 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7ZNJ	ELECTRON MICROSCOPY	2.4
3ULH	X-RAY DIFFRACTION	2.54
7ZNK	ELECTRON MICROSCOPY	3.9
8R7L	ELECTRON MICROSCOPY	4.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86V81-F1	65.65	0.25

Functional residue map

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

Post-translational modifications (18): 2, 8, 38, 38, 58, 63, 71, 86, 94, 141, 197, 197, 204, 204, 204, 220, 235, 239

Mutagenesis-validated functional residues (5):

Position	Phenotype
87	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-92.
92	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-87.
115	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with 139-y–r-144 del and 1
139–144	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-115 and 165-e–a-170
165–170	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-115 and 139-y–r-144

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-159227	Transport of the SLBP independent Mature mRNA
R-HSA-159230	Transport of the SLBP Dependant Mature mRNA
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72187	mRNA 3’-end processing
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-73856	RNA Polymerase II Transcription Termination

MSigDB gene sets: 175 (showing top): GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NUCLEAR_TRANSPORT, GOBP_REGULATION_OF_CATABOLIC_PROCESS, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, GOBP_OSSIFICATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, BASAKI_YBX1_TARGETS_UP, GOBP_NUCLEAR_EXPORT

GO Biological Process (6): osteoblast differentiation (GO:0001649), mRNA processing (GO:0006397), RNA export from nucleus (GO:0006405), mRNA export from nucleus (GO:0006406), RNA splicing (GO:0008380), mRNA transport (GO:0051028)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), C5-methylcytidine-containing RNA reader activity (GO:0062153), nucleic acid binding (GO:0003676)

GO Cellular Component (9): transcription export complex (GO:0000346), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), extracellular exosome (GO:0070062), catalytic step 2 spliceosome (GO:0071013)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	3
Transport of Mature Transcript to Cytoplasm	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	1
Dengue Virus Infection	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA processing	2
RNA transport	2
RNA binding	2
ossification	1
cell differentiation	1
mRNA metabolic process	1
nuclear export	1
RNA export from nucleus	1
gene expression	1
mRNA transport	1
nucleic acid binding	1
protein-RNA adaptor activity	1
binding	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
extracellular vesicle	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1

Protein interactions and networks

STRING

3232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALYREF	DDX39B	Q13838	999
ALYREF	THOC2	Q8NI27	992
ALYREF	SARNP	P82979	990
ALYREF	NXF1	Q9UBU9	988
ALYREF	THOC1	Q96FV9	985
ALYREF	NCBP1	Q09161	980
ALYREF	RNPS1	Q15287	970
ALYREF	EIF4A3	P38919	966
ALYREF	THOC3	Q96J01	963
ALYREF	SRRM1	Q8IYB3	916
ALYREF	TOP1	P11387	902
ALYREF	MAGOH	P50606	898
ALYREF	MAGOHB	Q96A72	894
ALYREF	UPF3B	Q9BZI7	878
ALYREF	RBM8A	Q9Y5S9	878

IntAct

317 interactions, top by confidence:

A	B	Type	Score
HNRNPC	HNRNPA1	psi-mi:“MI:0914”(association)	0.790
DDX39B	ALYREF	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NXF1	ALYREF	psi-mi:“MI:0915”(physical association)	0.660
AKT1	ALYREF	psi-mi:“MI:0407”(direct interaction)	0.640
AKT1	ALYREF	psi-mi:“MI:0915”(physical association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
	ALYREF	psi-mi:“MI:0915”(physical association)	0.620
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
ALYREF	UPF1	psi-mi:“MI:0914”(association)	0.530
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
CDK1	ALYREF	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
	ALYREF	psi-mi:“MI:0915”(physical association)	0.400
DDX5	ALYREF	psi-mi:“MI:0915”(physical association)	0.400
ALYREF	SUB2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (564): ALYREF (Biochemical Activity), AKT1 (Affinity Capture-Western), ALYREF (Affinity Capture-Western), AKT1 (Reconstituted Complex), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS), ALYREF (Affinity Capture-MS)

ESM2 similar proteins: B2GV05, B5FXN8, G3V9R8, O08583, O75525, O77768, P07910, P19600, P23588, P52756, P55795, P70333, P97379, P97855, Q08DJ0, Q0VFL7, Q13148, Q13283, Q1RMU5, Q28FB9, Q32LC7, Q3SZF3, Q3T0I4, Q58EA2, Q5R5W2, Q5R9L3, Q5RA82, Q5RB87, Q5RD26, Q5SRX1, Q5VWX1, Q5ZLN5, Q60HC3, Q64012, Q6AY09, Q6GLW1, Q86SE5, Q86V81, Q8BGD9, Q8BTF8

Diamond homologs: A0A0D1C8Z4, A0A0D1DZT6, A2RVS6, A5DM21, A5DW14, B5FXN8, F1QB54, F4HT49, F4I3B3, F4JHI7, G3V6S8, O08583, O13845, O22315, O35326, O59670, O74400, P04147, P19682, P19683, P19684, P20965, P49313, P49314, P78814, P82277, P97855, Q04836, Q08170, Q08935, Q08937, Q09167, Q13242, Q13243, Q13247, Q13283, Q14498, Q1ZXC2, Q28FB9, Q32LC7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	ALYREF	phosphorylation
AKT1	up-regulates	ALYREF	phosphorylation
ALYREF	“form complex”	“TREX complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metabolism of non-coding RNA	6	28.6×	2e-06
Processing of Intronless Pre-mRNAs	5	21.5×	8e-05
mRNA 3’-end processing	14	20.7×	3e-13
RNA Polymerase II Transcription Termination	12	19.8×	5e-11
Transport of Mature Transcript to Cytoplasm	6	17.2×	4e-05
Processing of Capped Intron-Containing Pre-mRNA	24	14.8×	3e-19
mRNA Polyadenylation	22	14.5×	2e-17
mRNA Splicing	17	14.0×	3e-13

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal snRNP assembly	9	32.7×	1e-09
U2-type prespliceosome assembly	7	27.3×	8e-07
alternative mRNA splicing, via spliceosome	6	25.3×	2e-05
mRNA export from nucleus	13	24.0×	2e-12
mRNA splicing, via spliceosome	33	18.9×	6e-30
spliceosomal complex assembly	5	18.8×	6e-04
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	5	14.6×	2e-03
RNA splicing	23	12.7×	2e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	6
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3391935	GRCh37/hg19 17q25.3(chr17:79663142-81041938)x1	Pathogenic

SpliceAI

848 predictions. Top by Δscore:

Variant	Effect	Δscore
17:81888239:A:AC	donor_gain	1.0000
17:81888240:C:CC	donor_gain	1.0000
17:81888240:CT:C	donor_gain	1.0000
17:81888240:CTCT:C	donor_gain	1.0000
17:81888415:TACG:T	acceptor_gain	1.0000
17:81888417:CG:C	acceptor_gain	1.0000
17:81888419:C:CC	acceptor_gain	1.0000
17:81888519:CCT:C	donor_gain	1.0000
17:81889177:CTCA:C	donor_loss	1.0000
17:81889178:TCA:T	donor_loss	1.0000
17:81889179:CA:C	donor_loss	1.0000
17:81889180:A:AC	donor_gain	1.0000
17:81889180:A:C	donor_loss	1.0000
17:81889180:AC:A	donor_gain	1.0000
17:81889180:ACCAT:A	donor_gain	1.0000
17:81889181:C:CC	donor_gain	1.0000
17:81889181:CC:C	donor_gain	1.0000
17:81889181:CCA:C	donor_gain	1.0000
17:81889181:CCAT:C	donor_gain	1.0000
17:81889181:CCATC:C	donor_gain	1.0000
17:81889325:AGTTC:A	acceptor_gain	1.0000
17:81889326:GTTC:G	acceptor_gain	1.0000
17:81889327:TTC:T	acceptor_gain	1.0000
17:81889328:TC:T	acceptor_gain	1.0000
17:81889329:CC:C	acceptor_gain	1.0000
17:81889329:CCTG:C	acceptor_loss	1.0000
17:81889330:C:CC	acceptor_gain	1.0000
17:81889330:C:CG	acceptor_loss	1.0000
17:81889331:T:C	acceptor_loss	1.0000
17:81889337:T:C	acceptor_gain	1.0000

AlphaMissense

1691 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000144064 (17:81892449 A>G), RS1000262493 (17:81893374 G>A,C), RS1000428640 (17:81892765 C>T), RS1000477458 (17:81890958 G>A), RS1000772839 (17:81887466 T>C), RS1001531998 (17:81890257 T>C), RS1001635435 (17:81893103 G>C), RS1001842265 (17:81892257 C>A), RS1001937175 (17:81892134 C>A,G,T), RS1001973817 (17:81891825 G>T), RS1002365022 (17:81891662 G>A), RS1002490307 (17:81888812 G>A,T), RS1002588419 (17:81890441 C>T), RS1003363264 (17:81892824 A>G), RS1003518315 (17:81891604 C>G,T)

Disease associations

OMIM: gene MIM:604171 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296014 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.35	Kd	4451	nM	CHEMBL5653589
5.35	ED50	4451	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147848: Binding affinity to human ALYREF incubated for 45 mins by Kinobead based pull down assay	kd	4.4509	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression, affects expression	4
bisphenol F	increases expression, affects cotreatment	3
bisphenol S	increases expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
lead acetate	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
versicolorin A	increases expression	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
phenanthrene	decreases expression	1
perfluorodecanoic acid	increases expression	1
yessotoxin	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	affects response to substance	1
Caffeine	increases phosphorylation	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118564	Binding	Binding affinity to ALYREF in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7VZ	Abcam Raji ALYREF KO	Cancer cell line	Male
CVCL_B9WH	Abcam THP-1 ALYREF KO	Cancer cell line	Male
CVCL_C6YI	Abcam PC-3 ALYREF KO	Cancer cell line	Male

Clinical trials (associated diseases)

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