PSME3

Summary

PSME3 (proteasome activator subunit 3, HGNC:9570) is a protein-coding gene on chromosome 17q21.31, encoding Proteasome activator complex subunit 3 (P61289). Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-prefe…. It is a selective cancer dependency (DepMap: 12.1% of cell lines).

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. The immunoproteasome contains an alternate regulator, referred to as the 11S regulator or PA28, that replaces the 19S regulator. Three subunits (alpha, beta and gamma) of the 11S regulator have been identified. This gene encodes the gamma subunit of the 11S regulator. Six gamma subunits combine to form a homohexameric ring. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10197 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 34 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 12.1% of screened cell lines
• MANE Select transcript: NM_005789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9570
Approved symbol	PSME3
Name	proteasome activator subunit 3
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	Ki, PA28-gamma, REG-GAMMA, PA28G
Ensembl gene	ENSG00000131467
Ensembl biotype	protein_coding
OMIM	605129
Entrez	10197

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000293362, ENST00000441946, ENST00000541124, ENST00000543428, ENST00000545225, ENST00000585805, ENST00000586114, ENST00000586312, ENST00000589469, ENST00000590720, ENST00000591152, ENST00000591722, ENST00000592169, ENST00000592458, ENST00000592578, ENST00000593111, ENST00000905283, ENST00000905284, ENST00000933469, ENST00000933470, ENST00000933471, ENST00000933472, ENST00000968130

RefSeq mRNA: 4 — MANE Select: NM_005789 NM_001267045, NM_001330229, NM_005789, NM_176863

CCDS: CCDS11442, CCDS45689, CCDS59290, CCDS82133

Canonical transcript exons

ENST00000590720 — 11 exons

Exon	Start	End
ENSE00002780597	42833397	42833673
ENSE00002832104	42841498	42843760
ENSE00003542001	42838093	42838205
ENSE00003557560	42834344	42834376
ENSE00003568667	42834772	42834876
ENSE00003568921	42838731	42838799
ENSE00003592148	42839112	42839166
ENSE00003597908	42834515	42834577
ENSE00003613979	42839294	42839380
ENSE00003618249	42837649	42837697
ENSE00003713864	42838945	42839012

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 95.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.5583 / max 252.0555, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161000	53.5469	1825
161001	0.0114	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	95.39	gold quality
cortical plate	UBERON:0005343	95.11	gold quality
monocyte	CL:0000576	94.94	gold quality
stromal cell of endometrium	CL:0002255	94.77	gold quality
rectum	UBERON:0001052	94.58	gold quality
gastrocnemius	UBERON:0001388	94.49	gold quality
leukocyte	CL:0000738	94.48	gold quality
mononuclear cell	CL:0000842	94.43	gold quality
muscle of leg	UBERON:0001383	94.03	gold quality
vermiform appendix	UBERON:0001154	93.85	gold quality
esophagus mucosa	UBERON:0002469	93.55	gold quality
ganglionic eminence	UBERON:0004023	93.48	gold quality
mucosa of transverse colon	UBERON:0004991	93.42	gold quality
colonic epithelium	UBERON:0000397	93.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.01	gold quality
smooth muscle tissue	UBERON:0001135	92.97	gold quality
heart left ventricle	UBERON:0002084	92.84	gold quality
left testis	UBERON:0004533	92.80	gold quality
granulocyte	CL:0000094	92.76	gold quality
right testis	UBERON:0004534	92.68	gold quality
esophagus	UBERON:0001043	92.67	gold quality
ventricular zone	UBERON:0003053	92.67	gold quality
cardiac ventricle	UBERON:0002082	92.65	gold quality
prefrontal cortex	UBERON:0000451	92.61	gold quality
right adrenal gland	UBERON:0001233	92.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.41	gold quality
body of stomach	UBERON:0001161	92.40	gold quality
right adrenal gland cortex	UBERON:0035827	92.39	gold quality
adrenal tissue	UBERON:0018303	92.36	gold quality
skin of leg	UBERON:0001511	92.34	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	1144.05
E-MTAB-7008	no	577.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NCOA3, SMAD3, TP53

miRNA regulators (miRDB)

161 targeting PSME3, 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-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• PA28gamma is an endogenous substrate for caspase-3 and -7 (PMID:11859414)
• Ki antigen contains multiple epitopes recognized by autoimmune sera (PMID:12784391)
• PA28 gamma novel regulator of Cajal body integrity in response to ultraviolet radiation. (PMID:17088425)
• Overexpression of the proteasome activator subunit PA28gamma recovered proteasome function in Huntington disease cells. It improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors. (PMID:17327906)
• REGgamma proteasome activator is involved in the maintenance of chromosomal stability. (PMID:18235248)
• PA28gamma, a proteasome activator that inhibits apoptosis and promotes cell cycle progression through unknown mechanisms, exerts an effect as a cofactor in the MDM2-p53 interaction. (PMID:18309296)
• PA28gamma/REGgamma, which specifically binds to hepatitis c virus core protein, is required for the virulence of the core protein[review] (PMID:18321762)
• mammalian proteasomes cannot degrade glutamine-expanded regions within pathogenic polyQ-expanded proteins, such as Huntingtin (PMID:18343811)
• PA28gamma specifically binds to hepatitis C virus core protein and is involved in its degradation. (PMID:19091860)
• these results underline a new role for REGgamma in the control and regulation of promyelocytic leukemia subnuclear structures. (PMID:19556897)
• Data suggest REGgamma promoting tumor growth is a process involving multiple factor mechanisms. (PMID:19656465)
• High REGgamma expression is associated with breast cancer and its metastatic lymph nodes. (PMID:20467919)
• REGgamma is present in many tissues and the highest expression is in the testis. (PMID:20494959)
• PA28gamma participates not only in the pathogenesis but also in the propagation of HCV by regulating the degradation of the core protein in both a ubiquitin-dependent and ubiquitin-independent manner (PMID:20683941)
• REGgamma-mediated p53 proteolysis contributes, as least in part, to the proviral function of REGgamma; the host REGgamma pathway is utilized and modified during CVB3 infection to promote efficient viral replication (PMID:20719955)
• REGgamma regulates cellular distribution of p53 by facilitating its multiple monoubiquitylation and nuclear export. (PMID:21084564)
• HTLV-1 p30 interacts with ATM and REGgamma to increase viral spread by facilitating cell survival (PMID:21216954)
• A previously unrecognized mechanism regulating the activity of the proteasome activator REGgamma, is reported. (PMID:21445096)
• REG-gamma associates with and modulates the abundance of nuclear activation-induced deaminase. (PMID:22042974)
• PA28gamma is an ATM target, being recruited to DNA damage sites where it is required for rapid accumulation of proteasomes, and the timely coordination of DNA double-strand break repair. (PMID:22134242)
• statistical analysisof laryngeal carcinomas revealed that there was a positive relationship between the level of REGgamma and the expression of p53 and p2; study suggests that REgamma overexpression can facilitate the growth of laryngeal cancer cells (PMID:22938444)
• PA28gamma acts as a co-repressor of HTLV-1 p30 to suppress virus replication and is required for the maintenance of viral latency. (PMID:23104922)
• the regulation of REGgamma assembly and activity, suggesting a potential venue for the intervention of the ubiquitin-independent REGgamma proteasome activity. (PMID:23612972)
• Expression of PA28gamma contributes to carcinogenesis and progression of colorectal cancer. (PMID:24113729)
• The REGgamma-proteasome pathway is regulated differentially by p53/TGF-beta signaling and mutant p53 in cancer cells. (PMID:24157709)
• PA28 gamma and p53 form a negative feedback loop that maintains the balance of p53 and PA28gamma in the cells. (PMID:24531141)
• PKA turnover by the REGgamma-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis. (PMID:24560667)
• Data suggest levels of gene expression of both PSME3 (proteasome activator subunit 3) and DUSP3 (dual specificity phosphatase 3) are associated with susceptibility to Staphylococcus aureus infection/sepsis in humans and in mouse disease model. (PMID:24901344)
• The results link Chk2 and REGgamma to the mechanism underlying the DBC1-dependent SIRT1 inhibition. (PMID:25361978)
• Increased PA28gamma sera levels were prognostic of disease activity in rheumatoid arthritis. (PMID:25482151)
• REGgamma expression is positively correlated with ERalpha status and poor clinical prognosis in ERalpha positive breast cancer patients (PMID:25490392)
• Our data indicate that miR-7-5p has a critical function through blocking REGgamma in breast cancer cells. (PMID:25511742)
• Our results suggest that the high expression of REGgamma might predict metastasis and poor prognosis in breast cancer. (PMID:25550823)
• Examination of EC and normal endometrium specimens confirmed the oncogenic role of REGgamma, in that REGgamma was more highly overexpressed in p53-positive specimens than in p53-negative specimens. (PMID:25697482)
• REGgamma acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/beta-catenin pathway. (PMID:25908095)
• Results show molecular cloning of a novel transcript variant encoding a truncated form of PA28G likely involved in cell cycle regulation and apoptosis. (PMID:25936920)
• In a p53-dominated cellular context, pro-apoptotic signaling might be overcome by PA28gamma-mediated caspase inhibition. (PMID:26201457)
• Surrogate Prognostic Biomarkers in OSCC: The Paradigm of PA28gamma Overexpression. (PMID:26425675)
• PA28gamma in OSCC tumor tissues were significantly high expression than those in normal tissues. (PMID:26425691)
• Study demonstrated that the gene therapy with proteasome activator, PA28gamma can improve ubiquitin-proteasome system function as well as behavioral abnormalities in Huntington’s disease model mice (PMID:26944602)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	psme3	ENSDARG00000012234
mus_musculus	Psme3	ENSMUSG00000078652
drosophila_melanogaster	REG	FBGN0029133
caenorhabditis_elegans		WBGENE00013435

Paralogs (2): PSME1 (ENSG00000092010), PSME2 (ENSG00000100911)

Protein

Protein identifiers

Proteasome activator complex subunit 3 — P61289 (reviewed: P61289)

Alternative names: 11S regulator complex subunit gamma, Activator of multicatalytic protease subunit 3, Ki nuclear autoantigen, Proteasome activator 28 subunit gamma

All UniProt accessions (11): B3KQ25, B7Z8D3, P61289, K7EJF8, K7EKR3, K7EMD0, K7ENH2, K7EPX6, K7ESG5, K9J957, V9HWJ8

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition.

Subunit / interactions. Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3. Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome. Interacts with COIL; the interaction is inhibited by PSME3IP1. (Microbial infection) Interacts with human cytomegalovirus UL27.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Phosphorylated by MAP3K3. Phosphorylation at Ser-247 promotes its association with CCAR2. Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.

Domain organisation. The C-terminal sequences affect heptamer stability and proteasome affinity.

Induction. Up-regulated in thyroid carcinoma cells.

Similarity. Belongs to the PA28 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P61289-1	1	yes
P61289-2	2
P61289-3	3

RefSeq proteins (4): NP_001253974, NP_001317158, NP_005780, NP_789839 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003185	Proteasome_activ_PA28_N	Domain
IPR003186	PA28_C	Domain
IPR009077	Proteasome_activ_PA28	Family
IPR036252	Proteasome_activ_sf	Homologous_superfamily
IPR036996	PA28_N_sf	Homologous_superfamily
IPR036997	PA28_C_sf	Homologous_superfamily

Pfam: PF02251, PF02252

UniProt features (19 total): helix 6, modified residue 5, sequence conflict 2, splice variant 2, initiator methionine 1, chain 1, turn 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7YQC	ELECTRON MICROSCOPY	2.82
7YQD	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61289-F1	87.68	0.74

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 (5): 2, 17, 24, 195, 247

Mutagenesis-validated functional residues (1):

Position	Phenotype
188	assembles into less stable hexamers/heptamers and therefore impairs specificity of activation of trypsin-like subunits o

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9907900	Proteasome assembly

MSigDB gene sets: 276 (showing top): ELVIDGE_HYPOXIA_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, KEGG_PROTEASOME, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, WONG_PROTEASOME_GENE_MODULE, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, MUELLER_PLURINET, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, MYCMAX_01, GOBP_CILIUM_MOVEMENT

GO Biological Process (4): apoptotic process (GO:0006915), regulation of proteasomal protein catabolic process (GO:0061136), regulation of G1/S transition of mitotic cell cycle (GO:2000045), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237)

GO Molecular Function (5): p53 binding (GO:0002039), identical protein binding (GO:0042802), endopeptidase activator activity (GO:0061133), MDM2/MDM4 family protein binding (GO:0097371), protein binding (GO:0005515)

GO Cellular Component (9): proteasome complex (GO:0000502), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), proteasome activator complex (GO:0008537), membrane (GO:0016020), ciliary basal body (GO:0036064)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	3
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
G1/S transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
extrinsic apoptotic signaling pathway	1
negative regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
endopeptidase activity	1
peptidase activator activity	1
endopeptidase regulator activity	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
proteasome accessory complex	1
protein-containing complex	1
microtubule organizing center	1
cilium	1

Protein interactions and networks

STRING

2721 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSME3	NCOA3	Q9Y6Q9	917
PSME3	PSME4	Q14997	870
PSME3	PSMF1	Q92530	763
PSME3	PDXP	Q96GD0	693
PSME3	PSME3IP1	Q9GZU8	675
PSME3	PSMD14	O00487	657
PSME3	PSMB7	Q99436	648
PSME3	ECPAS	Q5VYK3	627
PSME3	TP53	P04637	620
PSME3	PSME1	Q06323	618
PSME3	PSMA1	P25786	617
PSME3	PSMB10	P40306	608
PSME3	CENPV	Q7Z7K6	596
PSME3	PSMB8	P28062	594
PSME3	PSMC2	P35998	593

IntAct

418 interactions, top by confidence:

A	B	Type	Score
PSME3	PSME3	psi-mi:“MI:0915”(physical association)	0.860
PSME3	PRKAB2	psi-mi:“MI:0915”(physical association)	0.840
PSME3	EAF1	psi-mi:“MI:0915”(physical association)	0.840
EAF1	PSME3	psi-mi:“MI:0915”(physical association)	0.840
PRKAB2	PSME3	psi-mi:“MI:0915”(physical association)	0.840
COIL	PSME3	psi-mi:“MI:0915”(physical association)	0.820
ZCCHC10	PSME3	psi-mi:“MI:0915”(physical association)	0.780
PSME3	BBS2	psi-mi:“MI:0915”(physical association)	0.780
PSME3	ZCCHC10	psi-mi:“MI:0915”(physical association)	0.780
TNFAIP8L1	PSME3	psi-mi:“MI:0915”(physical association)	0.720
PSME3	PFDN5	psi-mi:“MI:0915”(physical association)	0.720
PRR13	PSME3	psi-mi:“MI:0915”(physical association)	0.720
PSME3	TNFAIP8L1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (719): PSME3 (Affinity Capture-MS), PSME3 (Two-hybrid), PSME3 (Two-hybrid), PSME3 (Two-hybrid), PSME3 (Two-hybrid), PSME3 (Two-hybrid), DIP2A (Two-hybrid), FBXO7 (Two-hybrid), TXN2 (Two-hybrid), PRR13 (Two-hybrid), ZCCHC10 (Two-hybrid), EAF1 (Two-hybrid), TNFAIP8L1 (Two-hybrid), PSME3 (Affinity Capture-RNA), PSME3 (Affinity Capture-RNA)

ESM2 similar proteins: A0JPN6, A4IIZ9, A5WUL3, A8E5U3, F1R7R1, F4HPA7, F4HRV8, O43513, O57595, O75934, P61289, P61290, P61291, Q15528, Q2F7Z4, Q2TBN4, Q2YDF2, Q3B8I4, Q3T123, Q4R4V3, Q5BJ48, Q5E9K2, Q5F3J5, Q5PPY2, Q5RFD3, Q5RHQ8, Q5RKN3, Q5XIX8, Q5ZKF4, Q62276, Q62717, Q62739, Q68EF0, Q6GLR7, Q6GPR9, Q6GQ95, Q7ZV35, Q800L3, Q80TJ1, Q86UW7

Diamond homologs: P58238, P61289, P61290, P61291, P97371, P97372, Q06323, Q4R4V3, Q4U5R3, Q5E9G3, Q5F3J5, Q5RFD3, Q63797, Q63798, Q64L94, Q863Z0, Q967U1, Q9UL46

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CHEK2	“up-regulates activity”	PSME3	phosphorylation
PSME3	“down-regulates quantity by destabilization”	SIRT7	binding
PSME3	“up-regulates activity”	“26S Proteasome”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1138 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42833659:G:GT	donor_gain	1.0000
17:42834872:ATGGT:A	donor_gain	1.0000
17:42834873:TGGT:T	donor_gain	1.0000
17:42834874:GGTG:G	donor_gain	1.0000
17:42834875:GT:G	donor_gain	1.0000
17:42834877:G:GG	donor_gain	1.0000
17:42837646:TAGCC:T	acceptor_loss	1.0000
17:42837647:A:AG	acceptor_gain	1.0000
17:42837647:A:AT	acceptor_loss	1.0000
17:42837648:G:GT	acceptor_gain	1.0000
17:42837648:GC:G	acceptor_gain	1.0000
17:42837648:GCC:G	acceptor_gain	1.0000
17:42837648:GCCC:G	acceptor_gain	1.0000
17:42837648:GCCCA:G	acceptor_gain	1.0000
17:42837693:CCAAG:C	donor_loss	1.0000
17:42837695:AAGGT:A	donor_loss	1.0000
17:42837698:G:GG	donor_gain	1.0000
17:42837698:GTA:G	donor_loss	1.0000
17:42837699:T:A	donor_loss	1.0000
17:42838082:A:AG	acceptor_gain	1.0000
17:42838083:T:G	acceptor_gain	1.0000
17:42838087:T:A	acceptor_gain	1.0000
17:42838088:GCCA:G	acceptor_loss	1.0000
17:42838091:A:AG	acceptor_gain	1.0000
17:42838092:G:GA	acceptor_gain	1.0000
17:42838092:GGA:G	acceptor_gain	1.0000
17:42838092:GGAAC:G	acceptor_gain	1.0000
17:42838193:GAAAT:G	donor_gain	1.0000
17:42838283:G:GA	donor_gain	1.0000
17:42838728:CAGGT:C	acceptor_loss	1.0000

AlphaMissense

1683 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42834515:G:C	A26P	1.000
17:42834528:T:A	V30E	1.000
17:42834540:T:C	F34S	1.000
17:42834561:T:C	L41P	1.000
17:42838144:T:C	L115P	1.000
17:42838169:A:C	K123N	1.000
17:42838169:A:T	K123N	1.000
17:42838180:G:C	R127P	1.000
17:42838197:T:C	C133R	1.000
17:42838198:G:A	C133Y	1.000
17:42838199:T:G	C133W	1.000
17:42838202:C:A	N134K	1.000
17:42838202:C:G	N134K	1.000
17:42838732:T:A	V136D	1.000
17:42838734:A:G	K137E	1.000
17:42838736:A:C	K137N	1.000
17:42838736:A:T	K137N	1.000
17:42838738:T:A	M138K	1.000
17:42838738:T:G	M138R	1.000
17:42838740:T:A	W139R	1.000
17:42838740:T:C	W139R	1.000
17:42838742:G:C	W139C	1.000
17:42838742:G:T	W139C	1.000
17:42838747:A:C	Q141P	1.000
17:42838750:T:C	L142P	1.000
17:42838753:T:C	L143P	1.000
17:42838756:T:A	I144N	1.000
17:42838756:T:C	I144T	1.000
17:42838756:T:G	I144S	1.000
17:42838758:C:A	P145T	1.000

dbSNP variants (sampled 300 via entrez): RS1000095724 (17:42835176 T>A), RS1001499201 (17:42833668 C>T), RS1001516344 (17:42832956 T>A,C), RS1002029157 (17:42833185 C>A,T), RS1002255370 (17:42841380 A>G), RS1002510540 (17:42834066 C>G), RS1002626624 (17:42834470 C>A,G), RS1002688298 (17:42843613 T>C), RS1003005403 (17:42840501 G>A,T), RS1003269101 (17:42832002 A>T), RS1003326370 (17:42831656 G>A), RS1003408271 (17:42839570 T>A,C), RS1003431717 (17:42838040 G>A,T), RS1003526857 (17:42840816 A>G), RS1005001193 (17:42836385 T>C)

Disease associations

OMIM: gene MIM:605129 | 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): CHEMBL4296023 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.26	Kd	55.25	nM	CHEMBL5653589
7.26	ED50	55.25	nM	CHEMBL5653589
7.08	Kd	84	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 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	2149135: Binding affinity to human PSME3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0553	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179157: Binding affinity against PSME3 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0840	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
bisphenol A	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	2
Estradiol	affects binding, increases reaction, increases expression	2
Nickel	increases expression	2
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
titanium dioxide	increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
CGP 52608	affects binding, increases reaction	1
pterostilbene	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	increases secretion, affects cotreatment	1
ICG 001	decreases expression	1
quinocetone	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
LDN 193189	decreases expression, affects cotreatment	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118624	Binding	Binding affinity to PSME3 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

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3F7	Abcam HEK293T PSME3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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