USP21

Summary

USP21 (ubiquitin specific peptidase 21, HGNC:12620) is a protein-coding gene on chromosome 1q23.3, encoding Ubiquitin carboxyl-terminal hydrolase 21 (Q9UK80). Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator.

This gene encodes a member of the C19 peptidase family, also known as family 2 of ubiquitin carboxy-terminal hydrolases. The encoded protein cleaves ubiquitin from ubiquitinated proteins for recycling in intracellular protein degradation. The encoded protein is also able to release NEDD8, a ubiquitin-like protein, from NEDD8-conjugated proteins. This gene has been referred to as USP16 and USP23 but is now known as USP21. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27005 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 90 total
• Druggable target: yes
• MANE Select transcript: NM_001014443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12620
Approved symbol	USP21
Name	ubiquitin specific peptidase 21
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	USP16
Ensembl gene	ENSG00000143258
Ensembl biotype	protein_coding
OMIM	604729
Entrez	27005

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000289865, ENST00000368001, ENST00000368002, ENST00000479344, ENST00000482385, ENST00000485277, ENST00000486299, ENST00000487163, ENST00000492950, ENST00000493054, ENST00000696603

RefSeq mRNA: 4 — MANE Select: NM_001014443 NM_001014443, NM_001319847, NM_001319848, NM_012475

CCDS: CCDS30920, CCDS81392

Canonical transcript exons

ENST00000368002 — 14 exons

Exon	Start	End
ENSE00001446103	161159500	161159678
ENSE00001510990	161160366	161160506
ENSE00003461622	161163555	161163619
ENSE00003469749	161165029	161165143
ENSE00003524118	161162270	161162390
ENSE00003563292	161162615	161162726
ENSE00003572416	161164835	161164942
ENSE00003618237	161164534	161164612
ENSE00003619578	161164164	161164250
ENSE00003632279	161162919	161163074
ENSE00003665938	161165357	161165723
ENSE00003709278	161162038	161162097
ENSE00003894977	161163878	161163981
ENSE00003895740	161160620	161161240

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4417 / max 75.1101, expressed in 1769 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6210	12.1183	1768
6211	0.1631	57
6209	0.1603	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.92	gold quality
right ovary	UBERON:0002118	93.66	gold quality
left ovary	UBERON:0002119	93.40	gold quality
granulocyte	CL:0000094	93.37	gold quality
cerebellar hemisphere	UBERON:0002245	93.26	gold quality
lower esophagus mucosa	UBERON:0035834	93.23	gold quality
cerebellar cortex	UBERON:0002129	93.13	gold quality
cortical plate	UBERON:0005343	92.95	gold quality
right lobe of thyroid gland	UBERON:0001119	92.88	gold quality
body of uterus	UBERON:0009853	92.87	gold quality
endocervix	UBERON:0000458	92.77	gold quality
ganglionic eminence	UBERON:0004023	92.73	gold quality
left lobe of thyroid gland	UBERON:0001120	92.53	gold quality
skin of abdomen	UBERON:0001416	92.40	gold quality
metanephros cortex	UBERON:0010533	91.97	gold quality
apex of heart	UBERON:0002098	91.94	gold quality
right frontal lobe	UBERON:0002810	91.92	gold quality
adenohypophysis	UBERON:0002196	91.85	gold quality
cerebellum	UBERON:0002037	91.81	gold quality
left uterine tube	UBERON:0001303	91.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.71	gold quality
skin of leg	UBERON:0001511	91.67	gold quality
ectocervix	UBERON:0012249	91.60	gold quality
lower esophagus	UBERON:0013473	91.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.58	gold quality
body of stomach	UBERON:0001161	91.56	gold quality
right coronary artery	UBERON:0001625	91.51	gold quality
thyroid gland	UBERON:0002046	91.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.40
E-GEOD-99795	no	74.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting USP21, 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-4283	100.00	66.42	2097
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4718	98.55	68.61	814

Literature-anchored findings (GeneRIF, showing 29)

• USP21 plays an important role in the down-regulation of TNFalpha-induced NF-kappaB activation through deubiquitinating RIP1. (PMID:19910467)
• Study report that USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8. (PMID:21399617)
• Study observed a reduction in the number of A549 cells developing a primary cilium upon serum starvation when USP21 was depleted with two independent siRNA oligos. (PMID:22298430)
• Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3 (PMID:23395819)
• The protein stability of IL-33 is maintained by USP21 through deubiquitination (PMID:25197364)
• Data show that SUMOylated BANP, E5R, and Nac1 (BEN) domain 3 (BEND3) stabilizes NoRC component TTF-1-interacting protein 5 (Tip5)via association with ubiquitin specific protease 21 (USP21) debiquitinase (PMID:26100909)
• Results from computational biology identified a cancer mutation that inactivates the nuclear export signals of the human deubiquitinase USP21, and leads to the aberrant accumulation of this protein in the nucleus. (PMID:27174732)
• USP21 binds to the promoter region of IL-8 and mediates transcriptional initiation, which regulates the stem-cell like property of human renal cell carcinoma (PMID:27259257)
• Data show that ubiquitin variants (Ubvs) that bind to USP2 or USP21 contain a similar core functional epitope, or “hot spot,” consisting mainly of positions that are conserved as the wild type sequence, but also some positions that prefer mutant sequences. (PMID:27436899)
• USP21 recruits and stabilises Gli1 at the centrosome. (PMID:27621083)
• USP21 specifically regulates the Lys48-linked polyubiquitination and stability of NANOG (PMID:27956178)
• a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses. (PMID:28254948)
• USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. (PMID:28743957)
• USP21-mediated deubiquitination and stabilization of MEK2 plays a critical role in hepatocellular carcinoma development. (PMID:29706623)
• USP21 binds and deubiquitinates FOXM1 in breast cancer cells. (PMID:30865895)
• USP21 modulates Goosecoid function through deubiquitination. (PMID:31253698)
• work identifies and validates USP21 as a PDAC oncogene (PMID:31488580)
• The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer. (PMID:31956270)
• USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase-dependent manner. (PMID:33052017)
• USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B-cell lymphoma. (PMID:33389794)
• Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21. (PMID:33582217)
• Deubiquitinating Enzyme USP21 Inhibits HIV-1 Replication by Downregulating Tat Expression. (PMID:33827943)
• Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes. (PMID:34523817)
• USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer. (PMID:34825342)
• USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1. (PMID:35974001)
• USP21 accelerates the proliferation and glycolysis of esophageal cancer cells by regulating the STAT3/FOXO1 pathway. (PMID:36095935)
• Salt-like transcription factor 4 promotes laryngeal cancer progression through transcriptional activation of ubiquitin-specific protease 21 to stabilize Yin Yang 1. (PMID:36285444)
• c-JUN-induced upregulation of LINC00174 contributes to colorectal cancer proliferation and invasion through accelerating USP21 expression. (PMID:37434557)
• Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling. (PMID:37964466)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp21	ENSDARG00000094280
mus_musculus	Usp21	ENSMUSG00000053483
rattus_norvegicus	Usp21	ENSRNOG00000038347
drosophila_melanogaster	Usp2	FBGN0031187

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 21 — Q9UK80 (reviewed: Q9UK80)

Alternative names: Deubiquitinating enzyme 21, Ubiquitin thioesterase 21, Ubiquitin-specific-processing protease 21

All UniProt accessions (6): Q9UK80, A0A1W2PQ32, A0A1W2PRX0, A0A8Q3SIU3, V9GY36, V9GYJ6

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A releaves the repression of di- and trimethylation of histone H3 at ‘Lys-4’, resulting in regulation of transcriptional initiation. Regulates gene expression via histone H2A deubiquitination. Deubiquitinates BAZ2A/TIP5 leading to its stabilization. Also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates. Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination.

Subunit / interactions. Interacts with BEND3.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in heart, pancreas and skeletal muscle. Also expressed in brain, placenta, liver and kidney, and at very low level in lung.

Similarity. Belongs to the peptidase C19 family. USP21 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UK80-1	1	yes
Q9UK80-2	2
Q9UK80-3	3

RefSeq proteins (4): NP_001014443, NP_001306776, NP_001306777, NP_036607 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443

Enzyme classification (BRENDA):

• EC 3.4.19.12 — ubiquitinyl hydrolase 1 (BRENDA: 30 organisms, 328 substrates, 173 inhibitors, 70 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
UBIQUITIN-7-AMIDO-4-METHYLCOUMARIN	—	7
DABCYL-FKKKGGGDVKE-EDANS	0.0142–0.0616	6
UBIQUITIN 7-AMIDO-4-METHYLCOUMARIN	—	5
UBIQUITIN ETHYL ESTER	0.0006–0.03	5
DABCYL-FRLKGGAPIKGV-EDANS	0.0048–0.0217	3
UBIQUITIN-W-G75A	0.0001–0.0004	2
UBIQUITIN-W-G76A	0.0011–0.002	2
UBIQUITIN-W-H68A	0.0005	2
UBIQUITIN-W-I44A	0.0003–0.0004	2
UBIQUITIN-W-K11A	0.0011–0.0023	2
UBIQUITIN-W-K48A	0.0003–0.0007	2
UBIQUITIN-W-K63A	0.0004–0.0008	2
UBIQUITIN-W-K6A	0.0009–0.0014	2
UBIQUITIN-W-L71A	0.008–0.0198	2
UBIQUITIN-W-L73A	0.0058–0.0104	2

UniProt features (51 total): strand 14, helix 13, binding site 4, splice variant 3, sequence variant 3, sequence conflict 3, compositionally biased region 3, active site 2, chain 1, domain 1, mutagenesis site 1, region of interest 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3I3T	X-RAY DIFFRACTION	2.59
2Y5B	X-RAY DIFFRACTION	2.7
3MTN	X-RAY DIFFRACTION	2.7
9NY4	ELECTRON MICROSCOPY	2.98

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK80-F1	70.70	0.52

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): 221 (nucleophile); 518 (proton acceptor)

Ligand- & substrate-binding residues (4): 387; 437; 440; 384

Mutagenesis-validated functional residues (1):

Position	Phenotype
221	abolishes ubiquitin thioesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 289 (showing top): GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_PROTEIN_HOMOTETRAMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, PATIL_LIVER_CANCER, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_ORGANELLE_FISSION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (7): proteolysis (GO:0006508), protein deubiquitination (GO:0016579), transcription initiation-coupled chromatin remodeling (GO:0045815), chromatin organization (GO:0006325), ribosome disassembly (GO:0032790), positive regulation of DNA-templated transcription (GO:0045893), rescue of stalled cytosolic ribosome (GO:0072344)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), cysteine-type deubiquitinase activity (GO:0004843), cysteine-type peptidase activity (GO:0008234), deNEDDylase activity (GO:0019784), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	3
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of gene expression, epigenetic	1
cellular component organization	1
organelle disassembly	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cytoplasmic translational elongation	1
ribosome disassembly	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
peptidase activity	1
ubiquitin-like protein peptidase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP21	NEDD8	Q15843	677
USP21	RIPK1	Q13546	672
USP21	UCHL3	P15374	656
USP21	MYSM1	Q5VVJ2	630
USP21	H2AC20	Q16777	604
USP21	H2AC19	P20670	603
USP21	ZUP1	Q96AP4	555
USP21	GATA3	P23771	525
USP21	CYLD	Q9NQC7	518
USP21	OTULIN	Q96BN8	484
USP21	USP28	Q96RU2	478
USP21	ARL16	Q0P5N6	472
USP21	BRCC3	P46736	464
USP21	USP25	Q9UHP3	449
USP21	OTUB1	Q96FW1	439

IntAct

79 interactions, top by confidence:

A	B	Type	Score
UCHL1	USP21	psi-mi:“MI:0915”(physical association)	0.670
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
USP21	KRT40	psi-mi:“MI:0915”(physical association)	0.560
KRT40	USP21	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	USP21	psi-mi:“MI:0915”(physical association)	0.560
CPSF6	USP21	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	USP21	psi-mi:“MI:0915”(physical association)	0.560
KCTD9	USP21	psi-mi:“MI:0915”(physical association)	0.560
HOXC10	USP21	psi-mi:“MI:0915”(physical association)	0.560
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
Dlg4	USP21	psi-mi:“MI:0407”(direct interaction)	0.440
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
USP21	ANKRD28	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAH	FOXO6	psi-mi:“MI:0914”(association)	0.350
USP21	DCLK1	psi-mi:“MI:0915”(physical association)	0.000
USP21	SIPA1L1	psi-mi:“MI:0915”(physical association)	0.000
USP21	KIF1C	psi-mi:“MI:0915”(physical association)	0.000
USP21	GIGYF1	psi-mi:“MI:0915”(physical association)	0.000
USP21	NADK	psi-mi:“MI:0915”(physical association)	0.000
USP21	AFDN	psi-mi:“MI:0915”(physical association)	0.000
USP21	HDAC4	psi-mi:“MI:0915”(physical association)	0.000
USP21	MELK	psi-mi:“MI:0915”(physical association)	0.000
USP21	TBC1D25	psi-mi:“MI:0915”(physical association)	0.000
USP21	PLEKHA7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (228): USP21 (Affinity Capture-Western), IL33 (Affinity Capture-Western), USP21 (Affinity Capture-Western), UBC (Biochemical Activity), HIST2H2AA3 (Biochemical Activity), KRT40 (Two-hybrid), UBC (Biochemical Activity), USP21 (Affinity Capture-Western), USP21 (Affinity Capture-Western), AURKA (Biochemical Activity), NANOG (Affinity Capture-Western), USP21 (Affinity Capture-Western), NANOG (Reconstituted Complex), NANOG (Biochemical Activity), USP21 (Biochemical Activity)

ESM2 similar proteins: A0A8I3NFE2, A0JM59, A2BGT0, A5PJS6, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, B2GUX4, D2HBJ8, D7PF45, E7F6T8, E9QG68, O15357, O88974, P52479, Q0V9G5, Q14694, Q15047, Q1RMU2, Q28CN3, Q3KR59, Q5R5Z6, Q5RED8, Q5REG5, Q5XGZ2, Q5ZJN4, Q64127, Q66H62, Q6NTR6, Q6P549, Q70CQ3, Q70CQ4, Q70EK9, Q7ZUM8, Q80TQ2, Q8BW70, Q8C2S0

Diamond homologs: A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6H8I0, A6NNY8, A6QNM7, A7TGY3, A7Z056, B1WBD7, B2GUX4, B2GUZ1, B3NC86, B4KXJ5, B4LG38, D2HBJ8, E9Q9U0, F8VPZ3, M9PD06, O22207, O57429, O60079, O94269, O94966, O96612, P0C8Z3, P35125, P39538, P51784, P53874, Q01988, Q0E2F9, Q0V9G5, Q28CN3, Q2HJE4, Q2KJ72, Q2LZB1, Q3UJD6, Q3V0C5, Q5D006

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MAPK14	“up-regulates activity”	USP21	phosphorylation
USP21	“down-regulates activity”	STING1	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
MITF-M-regulated melanocyte development	5	12.4×	7e-04
CDC42 GTPase cycle	7	11.0×	9e-05
RHO GTPase cycle	7	9.2×	3e-04
RHO GTPase Effectors	6	8.9×	8e-04
Signaling by Rho GTPases	11	8.2×	9e-06
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	11	8.0×	9e-06
Transcriptional Regulation by TP53	5	6.8×	6e-03
Membrane Trafficking	8	6.5×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2093 predictions. Top by Δscore:

Variant	Effect	Δscore
1:161160970:TTCC:T	donor_gain	1.0000
1:161160976:GTCT:G	donor_gain	1.0000
1:161162260:T:A	acceptor_gain	1.0000
1:161162265:CCCA:C	acceptor_loss	1.0000
1:161162266:CCAGT:C	acceptor_loss	1.0000
1:161162268:A:AG	acceptor_gain	1.0000
1:161162268:AGT:A	acceptor_gain	1.0000
1:161162269:G:GG	acceptor_gain	1.0000
1:161162269:G:GT	acceptor_loss	1.0000
1:161162269:GT:G	acceptor_gain	1.0000
1:161162269:GTG:G	acceptor_gain	1.0000
1:161162269:GTGC:G	acceptor_gain	1.0000
1:161162387:GAAGG:G	donor_loss	1.0000
1:161162388:AAGGT:A	donor_loss	1.0000
1:161162389:AGGTG:A	donor_loss	1.0000
1:161162391:G:C	donor_loss	1.0000
1:161162599:A:AG	acceptor_gain	1.0000
1:161162613:A:AG	acceptor_gain	1.0000
1:161162614:G:GA	acceptor_gain	1.0000
1:161162910:T:TA	acceptor_gain	1.0000
1:161162911:G:A	acceptor_gain	1.0000
1:161162914:T:A	acceptor_gain	1.0000
1:161162915:GTAGC:G	acceptor_loss	1.0000
1:161162917:A:AG	acceptor_gain	1.0000
1:161162918:G:GT	acceptor_gain	1.0000
1:161162918:GC:G	acceptor_gain	1.0000
1:161162918:GCC:G	acceptor_gain	1.0000
1:161162918:GCCA:G	acceptor_gain	1.0000
1:161163070:T:G	donor_gain	1.0000
1:161163070:TTAAG:T	donor_gain	1.0000

AlphaMissense

3588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:161162074:G:C	G213R	1.000
1:161162075:G:A	G213D	1.000
1:161162078:T:A	L214H	1.000
1:161162083:A:G	N216D	1.000
1:161162085:C:A	N216K	1.000
1:161162085:C:G	N216K	1.000
1:161162090:G:A	G218E	1.000
1:161162090:G:T	G218V	1.000
1:161162093:A:T	N219I	1.000
1:161162094:C:A	N219K	1.000
1:161162094:C:G	N219K	1.000
1:161162273:T:A	F222I	1.000
1:161162273:T:C	F222L	1.000
1:161162275:C:A	F222L	1.000
1:161162275:C:G	F222L	1.000
1:161162281:T:A	N224K	1.000
1:161162281:T:G	N224K	1.000
1:161162294:T:C	C229R	1.000
1:161162296:T:G	C229W	1.000
1:161162681:T:C	F283S	1.000
1:161162926:G:C	D301H	1.000
1:161162927:A:C	D301A	1.000
1:161162927:A:G	D301G	1.000
1:161162927:A:T	D301V	1.000
1:161162928:T:A	D301E	1.000
1:161162928:T:G	D301E	1.000
1:161163582:G:C	W359C	1.000
1:161163582:G:T	W359C	1.000
1:161163608:G:T	S368I	1.000
1:161163889:G:C	G376R	1.000

dbSNP variants (sampled 300 via entrez): RS1000876078 (1:161159352 T>C,G), RS1001087345 (1:161165892 G>A), RS1001104796 (1:161159018 C>G), RS1001306250 (1:161157502 G>A), RS1002071132 (1:161161325 C>A,G,T), RS1002264879 (1:161161885 T>C), RS1002706050 (1:161165138 C>T), RS1003929818 (1:161166162 T>A,C), RS1003983394 (1:161158311 C>G), RS1004583454 (1:161159592 G>A,C), RS1005039520 (1:161166182 G>A,T), RS1005532626 (1:161157988 T>C), RS1005565879 (1:161159407 G>GT), RS1005739854 (1:161164185 G>A,C), RS1005852266 (1:161158298 A>C,G,T)

Disease associations

OMIM: gene MIM:604729 | 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): CHEMBL2157852 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C19: Ubiquitin-specific protease

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
BAY-805	Inhibition	8.22	pIC50

ChEMBL bioactivities

30 potent at pChembl≥5 of 36 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.78	EC50	0.0166	nM	CHEMBL5279102
10.02	EC50	0.095	nM	CHEMBL5279102
8.70	IC50	2	nM	CHEMBL5279102
8.66	Kd	2.2	nM	CHEMBL5279102
8.24	Kd	5.8	nM	CHEMBL5286335
8.22	IC50	6	nM	CHEMBL5279102
8.10	IC50	8	nM	CHEMBL5268828
8.10	Kd	7.87	nM	CHEMBL5273043
7.96	IC50	11	nM	CHEMBL5286335
7.92	IC50	12	nM	CHEMBL5268828
7.75	IC50	18	nM	CHEMBL5286335
7.55	IC50	28	nM	CHEMBL5277351
7.50	IC50	32	nM	CHEMBL5277351
7.50	IC50	32	nM	CHEMBL5275560
7.50	IC50	32	nM	CHEMBL5267932
7.44	IC50	36	nM	CHEMBL5271965
7.35	IC50	45	nM	CHEMBL5271965
7.35	IC50	45	nM	CHEMBL5266176
7.19	IC50	65	nM	CHEMBL5279700
7.14	IC50	73	nM	CHEMBL5275560
7.14	IC50	72	nM	CHEMBL5280287
7.14	IC50	72	nM	CHEMBL5274527
7.13	IC50	74	nM	CHEMBL5275910
7.08	IC50	84	nM	CHEMBL5267932
7.00	IC50	100	nM	CHEMBL5266176
6.92	IC50	119	nM	CHEMBL5274527
6.66	IC50	221	nM	CHEMBL5278034
6.12	IC50	754	nM	CHEMBL5278034
5.23	IC50	5870	nM	CHEMBL5269090
5.15	IC50	7140	nM	CHEMBL5269090

PubChem BioAssay actives

30 with measured affinity, of 108 total; 15 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-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947440: Inhibition of full-length human USP21 transfected in human HEK293T cells co-transfected with NF-kappaB reporter firefly luciferase plasmid assessed as NF-kappaB activation and measured after 20 hrs by dual-luciferase reporter gene assay	ec50	<0.0001	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947414: Binding affinity to recombinant human N-terminal His6-tagged USP21 (209 to 563 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by SPR analysis	kd	0.0058	uM
N-[1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclopentanecarboxamide	1947414: Binding affinity to recombinant human N-terminal His6-tagged USP21 (209 to 563 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by SPR analysis	kd	0.0079	uM
N-[(1R)-2-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-cyclopentyl-2-oxoethyl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0080	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-ethylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0280	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(difluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0320	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0320	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0360	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-3-hydroxy-3-methyl-1-oxobutan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0450	uM
N-[(2R)-1-[[2-[(4-cyanophenyl)methyl]-4-methyl-1,3-thiazol-5-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0650	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-4-methyl-1,3-thiazol-2-yl]amino]-3-methoxy-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0720	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.0720	uM
N-[(2R)-3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]-1-methylcyclohexane-1-carboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	0.0740	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclohexanecarboxamide	1947411: Inhibition of human USP21 using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay	ic50	0.2210	uM
N-[3-methoxy-1-[[5-[(4-nitrophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-1-oxopropan-2-yl]cyclopentanecarboxamide	1947410: Inhibition of human full length USP21 using Btn-Ahx-PNIRFLD-K(Ubi)-LPQQT-GD-amide as substrate preincubated for 15 to 20 mins followed by substrate addition and measured after 25 mins by HTRF assay	ic50	5.8700	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects expression	3
moringin	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cannabidiol	increases expression	1
Doxorubicin	decreases expression	1
Gallic Acid	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression, increases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2163014	Binding	Inhibition of HIs6-tagged USP21 by Ub-CHOP reporter assay	Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47. — ACS Med Chem Lett

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KV	N/Tert-1 USP21	Telomerase immortalized cell line	Male
CVCL_D6BP	HyCyte Hep-G2 KO-hUSP21	Cancer cell line	Male
CVCL_D9VJ	Ubigene HEK293 USP21 KO	Transformed cell line	Female
CVCL_E2NJ	HAP1 USP21 (-) 3	Cancer cell line	Male
CVCL_E2NK	HAP1 USP21 (-) 4	Cancer cell line	Male
CVCL_E2NL	HAP1 USP21 (-) 5	Cancer cell line	Male
CVCL_TW74	HAP1 USP21 (-) 1	Cancer cell line	Male
CVCL_TW75	HAP1 USP21 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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