MUL1

Summary

MUL1 (mitochondrial E3 ubiquitin protein ligase 1, HGNC:25762) is a protein-coding gene on chromosome 1p36.12, encoding Mitochondrial ubiquitin ligase activator of NFKB 1 (Q969V5). Exhibits weak E3 ubiquitin-protein ligase activity.

Enables several functions, including p53 binding activity; ubiquitin protein ligase binding activity; and ubiquitin-like protein transferase activity. Involved in several processes, including cellular response to exogenous dsRNA; negative regulation of defense response; and regulation of mitochondrion organization. Located in several cellular components, including mitochondrial outer membrane; neuronal cell body; and peroxisome.

Source: NCBI Gene 79594 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 74 total
• MANE Select transcript: NM_024544

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25762
Approved symbol	MUL1
Name	mitochondrial E3 ubiquitin protein ligase 1
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12875, MULAN, RNF218, MAPL, GIDE
Ensembl gene	ENSG00000090432
Ensembl biotype	protein_coding
OMIM	612037
Entrez	79594

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000264198, ENST00000908517, ENST00000925240

RefSeq mRNA: 1 — MANE Select: NM_024544 NM_024544

CCDS: CCDS208

Canonical transcript exons

ENST00000264198 — 4 exons

Exon	Start	End
ENSE00000908639	20499448	20501419
ENSE00000908640	20502069	20502189
ENSE00000908641	20503222	20503309
ENSE00001041254	20507905	20508151

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 92.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9236 / max 47.7928, expressed in 1787 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10761	7.2319	1780
10760	0.6917	432

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	92.43	gold quality
heart left ventricle	UBERON:0002084	90.57	gold quality
cardiac ventricle	UBERON:0002082	90.33	gold quality
gastrocnemius	UBERON:0001388	90.21	gold quality
muscle of leg	UBERON:0001383	89.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.56	gold quality
mucosa of transverse colon	UBERON:0004991	88.98	gold quality
lower esophagus	UBERON:0013473	88.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.56	gold quality
islet of Langerhans	UBERON:0000006	88.50	gold quality
heart	UBERON:0000948	88.09	gold quality
stromal cell of endometrium	CL:0002255	87.88	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.71	gold quality
right atrium auricular region	UBERON:0006631	87.58	gold quality
muscle organ	UBERON:0001630	87.34	gold quality
cardiac atrium	UBERON:0002081	87.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.18	gold quality
lower esophagus mucosa	UBERON:0035834	87.08	gold quality
esophagus	UBERON:0001043	86.94	gold quality
transverse colon	UBERON:0001157	86.92	gold quality
right adrenal gland cortex	UBERON:0035827	86.72	gold quality
skin of leg	UBERON:0001511	86.46	gold quality
body of stomach	UBERON:0001161	86.36	gold quality
oocyte	CL:0000023	86.29	gold quality
right adrenal gland	UBERON:0001233	86.23	gold quality
left adrenal gland	UBERON:0001234	86.12	gold quality
esophagus mucosa	UBERON:0002469	85.95	gold quality
left adrenal gland cortex	UBERON:0035825	85.72	gold quality
right lobe of liver	UBERON:0001114	85.69	gold quality
gingival epithelium	UBERON:0001949	85.62	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting MUL1, 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-12118	100.00	65.88	1270
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6727-3P	99.49	65.92	1333

Literature-anchored findings (GeneRIF, showing 27)

• Confocal- and electron-microscopy studies of MAPL-YFP led to the observation that mitochondria-anchored protein ligase (MAPL) is incorporated within unique, DRP1-independent, 70-100 nm diameter mitochondria-derived vesicles (MDVs). (PMID:18207745)
• incorporated within unique, DRP1-independent, 70-100 nm diameter mitochondria-derived vesicles which fuse with a subset of peroxisomes (PMID:18207745)
• MULAN (Mitochondrial Ubiquitin Ligase Activator of NF-kB; aka FLJ12875, C1orf166) is a RING finger-type E3 ubiquitin ligase anchored to mitochondria that has been implicated in the regulation of mitochondrial dynamics and in the activation of NF-kB. (PMID:18213395)
• findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment (PMID:18213395)
• The identification of GIDE, a mitochondrially located E3 ubiquitin ligase, is reported. (PMID:18591963)
• The mitochondrial-anchored protein ligase (MAPL) is characterized as the first mitochondrial-anchored SUMO E3 ligase. (PMID:19407830)
• CARP and its regulator calpain 3 appear to occupy a central position in the important cell fate-governing NF-kappaB pathway in skeletal muscle (PMID:20860623)
• These findings show that Hades (MUL1)-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53 (PMID:21597459)
• MULAN negatively regulates Akt signaling, facilitating the control of multiple cellular processes. (PMID:22410793)
• MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation. (PMID:23399697)
• During stress-induced mitochondrial hyperfusion, MULAN forms a complex with TRAF2 and modulates its ubiquitylation, signifying that TRAF2 may serve as an ubiquitylated transmitter of NF-kappaB signaling in this pathway (PMID:24841215)
• MethyLight data demonstrated that C13orf18 and C1orf166 could not be considered as specific, sensitive and suitable prognostic biomarkers in cervical dysplasia related Papillomavirus Infections. (PMID:25169519)
• The interaction of GABARAP with Mulan-Ube2E3 supports the role of Mulan as an important regulator of mitophagy. (PMID:25224329)
• MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy (PMID:26018823)
• Cigarette smoke-induced MUL1 elevation mediates Akt ubiquitination/degradation, potentially leading to pulmonary endothelial cell death and functional impairment. (PMID:26203915)
• Activation of apoptosis triggers MAPL/MUL1-dependent SUMOylation of the fission GTPase Drp1, a process requisite for cytochrome c release. (PMID:26384664)
• Hades (MUL1)-mediated p73 ubiquitination is a novel regulatory mechanism for the exonuclear function of p73. (PMID:26435500)
• MULAN regulates NF-kappaappaB activation to protect cells from endoplasmic reticulum stress-induced apoptosis. (PMID:27082251)
• Data demonstrate a clear role for MAPL and mitochondrial SUMOylation in the activation of RIG-I, a modification essential for the mitochondrial antiviral signaling response. (PMID:28273895)
• HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer (PMID:29260979)
• The allele T in the rs529974(+) MUL1 gene was susceptible to Parkinson’s disease (PMID:30793286)
• These results provide a molecular basis for the novel recognition mechanism of the p53-transactivation domain substrate by the MUL1-RING domain. (PMID:31235254)
• The three-dimensional structures of MUL1-RING and of its complex with the cognate E2 enzyme has been determined. (PMID:31929179)
• Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1alpha) and metabolic reprogramming by modulating the UBXN7 cofactor protein. (PMID:32005965)
• A risk signature of three autophagy-related genes for predicting lower grade glioma survival is associated with tumor immune microenvironment. (PMID:33069830)
• A new functional role of mitochondria-anchored protein ligase in peroxisome morphology in mammalian cells. (PMID:34322908)
• MUL1 identified as mitochondria-linked biomarker promoting cisplatin resistance in OC cells. (PMID:39134101)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mul1	ENSDARG00000052527
mus_musculus	Mul1	ENSMUSG00000041241
rattus_norvegicus	Mul1	ENSRNOG00000016010
drosophila_melanogaster	Mul1	FBGN0035483
caenorhabditis_elegans		WBGENE00019649

Protein

Protein identifiers

Mitochondrial ubiquitin ligase activator of NFKB 1 — Q969V5 (reviewed: Q969V5)

Alternative names: E3 SUMO-protein ligase MUL1, E3 ubiquitin-protein ligase MUL1, Growth inhibition and death E3 ligase, Mitochondrial-anchored protein ligase, Protein Hades, Putative NF-kappa-B-activating protein 266, RING finger protein 218, RING-type E3 ubiquitin transferase NFKB 1

All UniProt accessions (1): Q969V5

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits weak E3 ubiquitin-protein ligase activity. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Can ubiquitinate AKT1 preferentially at ‘Lys-284’ involving ‘Lys-48’-linked polyubiquitination and seems to be involved in regulation of Akt signaling by targeting phosphorylated Akt to proteasomal degradation. Mediates polyubiquitination of cytoplasmic TP53 at ‘Lys-24’ which targets TP53 for proteasomal degradation, thus reducing TP53 levels in the cytoplasm and mitochondrion. Proposed to preferentially act as a SUMO E3 ligase at physiological concentrations. Plays a role in the control of mitochondrial morphology by promoting mitochondrial fragmentation, and influences mitochondrial localization. Likely to promote mitochondrial fission through negatively regulating the mitochondrial fusion proteins MFN1 and MFN2, acting in a pathway that is parallel to the PRKN/PINK1 regulatory pathway. May also be involved in the sumoylation of the membrane fission protein DNM1L. Inhibits cell growth. When overexpressed, activates JNK through MAP3K7/TAK1 and induces caspase-dependent apoptosis. Involved in the modulation of innate immune defense against viruses by inhibiting RIGI-dependent antiviral response. Can mediate RIGI sumoylation and disrupt its polyubiquitination.

Subunit / interactions. Homooligomer. Interacts with MAP3K7/TAK1. Interacts with UBC9. Interacts with and sumoylates DNM1L. Interacts with MAVS. Interacts with TP53 (via N-terminus); the interaction leads to ubiquitination and proteasomal degradation of TP53. Interacts with ABCB10, BAG6, CCDC51, MTCH1, MTCH2 and TRABD. Interacts with TOM complex.

Subcellular location. Mitochondrion outer membrane. Peroxisome.

Tissue specificity. Widely expressed with highest levels in the heart, skeletal muscle, placenta, kidney and liver. Barely detectable in colon and thymus.

Post-translational modifications. Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.

Domain organisation. The zinc finger domain is required for E3 ligase activity.

Pathway. Protein modification; protein ubiquitination. Protein modification; protein sumoylation.

RefSeq proteins (1): NP_078820* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR022170	MUL1-like	Domain
IPR051652	MDM2_MDM4_MUL1	Family

Pfam: PF12483, PF13920

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (27 total): mutagenesis site 6, strand 4, topological domain 3, turn 3, cross-link 3, sequence conflict 2, helix 2, transmembrane region 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6M2D	X-RAY DIFFRACTION	1.79
6M2C	X-RAY DIFFRACTION	2.7
6K2K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969V5-F1	90.05	0.72

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 (3): 52, 273, 299

Mutagenesis-validated functional residues (6):

Position	Phenotype
260	protein is targeted to the er; when associated with a-261.
261	protein is targeted to the er; when associated with a-260.
302	failure to reduce tp53 levels and abolishes ligase activity; when associated with s-305.
305	failure to reduce tp53 levels and abolishes ligase activity; when associated with s-302.
319	abolishes ligase activity. no effect on mitochondrial localization.
339	abolishes ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8951664	Neddylation
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress

MSigDB gene sets: 229 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_REGULATION_OF_PROTEIN_SUMOYLATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_GROWTH, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (28): protein polyubiquitination (GO:0000209), mitochondrial fission (GO:0000266), apoptotic process (GO:0006915), negative regulation of mitochondrial fusion (GO:0010637), regulation of mitochondrion organization (GO:0010821), protein ubiquitination (GO:0016567), protein sumoylation (GO:0016925), protein destabilization (GO:0031648), positive regulation of protein sumoylation (GO:0033235), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of innate immune response (GO:0045824), negative regulation of defense response to virus by host (GO:0050689), protein stabilization (GO:0050821), mitochondrion localization (GO:0051646), regulation of mitochondrial membrane potential (GO:0051881), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), cellular response to exogenous dsRNA (GO:0071360), negative regulation of chemokine (C-C motif) ligand 5 production (GO:0071650), positive regulation of mitochondrial fission (GO:0090141), regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway (GO:1901028), positive regulation of dendrite extension (GO:1903861), positive regulation of type 2 mitophagy (GO:1905091), organelle organization (GO:0006996), positive regulation of metabolic process (GO:0009893), regulation of anatomical structure morphogenesis (GO:0022603), regulation of protein stability (GO:0031647), positive regulation of developmental process (GO:0051094)

GO Molecular Function (10): p53 binding (GO:0002039), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), peroxisome (GO:0005777), membrane (GO:0016020), axon (GO:0030424), neuronal cell body (GO:0043025), TOM complex (GO:0140596)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Post-translational protein modification	2
Deubiquitination	1
Cellular response to chemical stress	1
Cellular responses to stimuli	1
Metabolism of proteins	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion organization	2
protein modification by small protein conjugation	2
regulation of protein stability	2
protein binding	2
ubiquitin-like protein transferase activity	2
protein ubiquitination	1
organelle fission	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
mitochondrial fusion	1
regulation of mitochondrial fusion	1
negative regulation of organelle organization	1
negative regulation of developmental process	1
regulation of organelle organization	1
peptidyl-lysine modification	1
protein sumoylation	1
regulation of protein sumoylation	1
positive regulation of protein modification by small protein conjugation or removal	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
negative regulation of immune response	1
negative regulation of defense response to virus	1
regulation of defense response to virus by host	1
organelle localization	1
regulation of membrane potential	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
response to exogenous dsRNA	1

Protein interactions and networks

STRING

1374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MUL1	NR6A1	Q15406	952
MUL1	UBE2D2	P51669	857
MUL1	MARCHF5	Q9NX47	786
MUL1	PINK1	Q9BXM7	734
MUL1	MAVS	Q7Z434	722
MUL1	PRKN	O60260	685
MUL1	MFN2	O95140	683
MUL1	USP30	Q70CQ3	654
MUL1	FUNDC1	Q8IVP5	649
MUL1	AKT2	P31751	639
MUL1	GABARAP	O95166	631
MUL1	BNIP3L	O60238	629
MUL1	DNM1L	O00429	619
MUL1	FIS1	Q9Y3D6	615
MUL1	VPS26A	O75436	612

IntAct

127 interactions, top by confidence:

A	B	Type	Score
ATRIP	ATR	psi-mi:“MI:0914”(association)	0.890
TSC2	YWHAH	psi-mi:“MI:0914”(association)	0.850
APPBP2	MUL1	psi-mi:“MI:0915”(physical association)	0.760
RANBP6	SLC27A2	psi-mi:“MI:0914”(association)	0.640
TBC1D9	ABHD16A	psi-mi:“MI:0914”(association)	0.640
COG7	ILVBL	psi-mi:“MI:0914”(association)	0.640
BZW2	ENDOD1	psi-mi:“MI:0914”(association)	0.640
BZW2	MUL1	psi-mi:“MI:0914”(association)	0.640
RANBP6	MUL1	psi-mi:“MI:0914”(association)	0.640
MUL1	TRIM9	psi-mi:“MI:0915”(physical association)	0.560
TRIM9	MUL1	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	MUL1	psi-mi:“MI:0915”(physical association)	0.560
MUL1	REEP2	psi-mi:“MI:0915”(physical association)	0.560
IPO11	BSG	psi-mi:“MI:0914”(association)	0.560
CNGA3	C2CD2L	psi-mi:“MI:0914”(association)	0.530
GSDME	SLC27A2	psi-mi:“MI:0914”(association)	0.530
BZW2	SLC27A2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
TRHDE	MAN1A2	psi-mi:“MI:0914”(association)	0.530
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PBXIP1	GOLIM4	psi-mi:“MI:0914”(association)	0.530

BioGRID (178): UBE2E2 (Two-hybrid), UBE2E3 (Two-hybrid), UBE2G2 (Two-hybrid), UBE2L3 (Two-hybrid), MUL1 (Affinity Capture-Western), TRIM9 (Two-hybrid), MUL1 (Affinity Capture-Western), ULK1 (Affinity Capture-Western), ULK1 (Reconstituted Complex), MUL1 (Affinity Capture-Western), ULK1 (Biochemical Activity), UBE2D1 (Reconstituted Complex), MUL1 (Affinity Capture-MS), MUL1 (Affinity Capture-MS), MUL1 (Affinity Capture-MS)

ESM2 similar proteins: A2AF53, A4FV75, A4QNE0, A5A6S6, A6QL84, A6ZIQ8, D3ZEH5, E1BD52, O57425, O60337, P56589, P58749, Q0P5I8, Q0VC58, Q2TBU2, Q2V4F9, Q3T0J1, Q3TMP8, Q4R5B4, Q4R7G8, Q5JZQ8, Q5M8Y1, Q5R8H8, Q5REE3, Q5RF53, Q5XIK2, Q5ZK43, Q6GLK9, Q6IC98, Q6NRL4, Q6ZQ89, Q7L5D6, Q7SYC7, Q80YV4, Q8CIF6, Q8NBJ9, Q8NFB2, Q8VCM5, Q8VIJ8, Q93ZQ5

Diamond homologs: A1E2V0, A1L020, A1L3F4, A2AWP0, A5D8Q0, A9JTP3, A9ULZ2, D3ZDI6, E3SCZ8, F4IDI6, O08863, O10324, O15392, O62640, O70201, O81851, O88738, P40629, P41454, P98170, Q05A36, Q05AK5, Q0WPJ7, Q13075, Q13489, Q13490, Q24307, Q28ER3, Q28H51, Q4R7G8, Q50L39, Q557E7, Q5BKL8, Q5E9J6, Q5NVC7, Q5R881, Q5RAH9, Q5U5Q3, Q5ZIJ9, Q60989

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
MUL1	“down-regulates quantity by destabilization”	AKT1	ubiquitination
MUL1	“down-regulates quantity by destabilization”	AKT	ubiquitination
Ub:E2	“up-regulates activity”	MUL1	ubiquitination
MUL1	“up-regulates activity”	DNM1L	sumoylation
MUL1	“up-regulates activity”	STING1	ubiquitination
MUL1	“down-regulates quantity”	ULK1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	6	24.3×	9e-05
Negative regulators of DDX58/IFIH1 signaling	5	17.9×	2e-03
E3 ubiquitin ligases ubiquitinate target proteins	6	12.8×	2e-03
Peroxisomal protein import	6	11.4×	2e-03
Antigen processing: Ubiquitination & Proteasome degradation	11	4.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	58
Likely benign	2
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

342 predictions. Top by Δscore:

Variant	Effect	Δscore
1:20501415:CATTC:C	acceptor_gain	1.0000
1:20501416:ATTC:A	acceptor_gain	1.0000
1:20501417:TTC:T	acceptor_gain	1.0000
1:20501418:TC:T	acceptor_gain	1.0000
1:20501418:TCCTA:T	acceptor_loss	1.0000
1:20501419:CC:C	acceptor_gain	1.0000
1:20501419:CCTAG:C	acceptor_loss	1.0000
1:20501420:C:CC	acceptor_gain	1.0000
1:20501420:CTA:C	acceptor_loss	1.0000
1:20501421:T:G	acceptor_loss	1.0000
1:20502065:ATACC:A	donor_loss	1.0000
1:20502066:TA:T	donor_loss	1.0000
1:20502067:A:AC	donor_gain	1.0000
1:20502067:ACCA:A	donor_loss	1.0000
1:20502068:C:CA	donor_gain	1.0000
1:20502068:CCAA:C	donor_gain	1.0000
1:20502187:CTC:C	acceptor_gain	1.0000
1:20502190:C:CC	acceptor_gain	1.0000
1:20502190:CTAA:C	acceptor_loss	1.0000
1:20502191:T:G	acceptor_loss	1.0000
1:20503217:CATA:C	donor_loss	1.0000
1:20503218:ATACC:A	donor_loss	1.0000
1:20503219:TA:T	donor_loss	1.0000
1:20503220:A:C	donor_loss	1.0000
1:20503221:C:CA	donor_loss	1.0000
1:20503305:GCTCC:G	acceptor_gain	1.0000
1:20503306:CTCC:C	acceptor_gain	1.0000
1:20503306:CTCCC:C	acceptor_gain	1.0000
1:20503307:TCC:T	acceptor_gain	1.0000
1:20503307:TCCCT:T	acceptor_gain	1.0000

AlphaMissense

2283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:20501120:A:G	L210P	0.998
1:20501147:A:G	L201P	0.998
1:20501153:C:T	G199D	0.998
1:20502120:C:G	R93P	0.998
1:20502155:G:C	S81R	0.998
1:20502155:G:T	S81R	0.998
1:20502157:T:G	S81R	0.998
1:20503222:C:G	G70R	0.998
1:20503222:C:T	G70R	0.998
1:20500743:A:G	C336R	0.997
1:20501183:A:G	L189P	0.997
1:20501366:A:G	L128P	0.997
1:20501371:A:C	F126L	0.997
1:20501371:A:T	F126L	0.997
1:20501372:A:G	F126S	0.997
1:20501373:A:G	F126L	0.997
1:20501419:C:A	W110C	0.997
1:20501419:C:G	W110C	0.997
1:20502070:A:G	W110R	0.997
1:20502070:A:T	W110R	0.997
1:20502111:A:G	L96P	0.997
1:20502117:A:G	L94P	0.997
1:20502133:C:G	G89R	0.997
1:20502133:C:T	G89R	0.997
1:20501147:A:T	L201Q	0.996
1:20501153:C:A	G199V	0.996
1:20501154:C:G	G199R	0.996
1:20501156:A:T	V198D	0.996
1:20501159:C:T	G197E	0.996
1:20501272:G:C	F159L	0.996

dbSNP variants (sampled 300 via entrez): RS1000118649 (1:20507739 G>A,T), RS1000469709 (1:20507424 T>C), RS1000697457 (1:20501600 T>C), RS1001635700 (1:20508087 T>C,G), RS1001649314 (1:20508301 G>A), RS1001918785 (1:20506427 T>A), RS1001981867 (1:20507842 T>C), RS1002372590 (1:20506753 G>A,C), RS1002582813 (1:20508861 C>A,T), RS1002961936 (1:20504948 C>T), RS1003043361 (1:20509140 C>T), RS1003319837 (1:20509512 T>A,C), RS1003560809 (1:20509630 C>G), RS1003864335 (1:20509657 C>T), RS1003877984 (1:20499548 CGA>C)

Disease associations

OMIM: gene MIM:612037 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010916_1	Proportion of activated microglia (inferior temporal cortex)	6.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Catechin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Silicon Dioxide	decreases methylation	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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