TFEB

Summary

TFEB (transcription factor EB, HGNC:11753) is a protein-coding gene on chromosome 6p21.1, encoding Transcription factor EB (P19484). Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response.

Enables DNA-binding transcription factor activity; enzyme binding activity; and transcription cis-regulatory region binding activity. Involved in several processes, including antibacterial innate immune response; cellular response to amino acid starvation; and regulation of lysosome organization. Located in cytosol and lysosomal membrane. Is active in nucleus.

Source: NCBI Gene 7942 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 42 total
• GTEx eGene: eQTL in 18 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.47 (moderately constrained)
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_001271944
• Interaction hub: 2,550 STRING partners (top 4% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11753
Approved symbol	TFEB
Name	transcription factor EB
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	TCFEB, bHLHe35
Ensembl gene	ENSG00000112561
Ensembl biotype	protein_coding
OMIM	600744
Entrez	7942

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 42 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000373033

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 2: 2, TSL 3: 2, TSL 5: 5

ENST00000373033, ENST00000230323, ENST00000343317, ENST00000358871, ENST00000394283, ENST00000403298, ENST00000406563, ENST00000416140, ENST00000419396, ENST00000419574, ENST00000420312, ENST00000424495, ENST00000445214, ENST00000494822, ENST00000677531, ENST00000678831, ENST00000678871, ENST00000679217, ENST00000679237, ENST00000861508, ENST00000861509, ENST00000861510, ENST00000861511, ENST00000861512, ENST00000861513, ENST00000861514, ENST00000861515, ENST00000861516, ENST00000861517, ENST00000861518, ENST00000861519, ENST00000861520, ENST00000861521, ENST00000941005, ENST00000941006, ENST00000941007, ENST00000941008, ENST00000941009, ENST00000941010, ENST00000941011, ENST00000941012, ENST00000941013, ENST00000941014, ENST00001000221, ENST00001000222, ENST00001027151, ENST00001027152

RefSeq mRNA: 5 — MANE Select: NM_001271944 NM_001167827, NM_001271943, NM_001271944, NM_001271945, NM_007162

CCDS: CCDS4858, CCDS64424, CCDS64425

Canonical transcript exons

ENST00000373033 — 9 exons

Exon	Start	End
ENSE00001404975	41683978	41685078
ENSE00001459373	41735350	41735608
ENSE00002032600	41687908	41688028
ENSE00002060005	41687753	41687809
ENSE00002078009	41686090	41686237
ENSE00002079173	41690663	41690917
ENSE00002087165	41689731	41689811
ENSE00003787517	41687094	41687169
ENSE00003791134	41691001	41691235

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 95.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9379 / max 148.7481, expressed in 1536 samples.

Highest expression (Bgee): type B pancreatic cell, hindlimb stylopod muscle, gastrocnemius, apex of heart, olfactory bulb.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TFEB is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellum	eqtl	1.1e-19	-0.53	6:41734844:C:T
Brain Cerebellar Hemisphere	eqtl	2.1e-16	+0.52	6:41741200:C:G
Nerve Tibial	eqtl	6.7e-08	-0.27	6:41733120:T:C
Cells Cultured fibroblasts	eqtl	2.4e-06	+0.22	6:41712509:A:G
Esophagus Muscularis	eqtl	4.8e-06	-0.22	6:41714748:C:T
Muscle Skeletal	sqtl	6.0e-06	-0.40	6:41683901:T:C
Esophagus Gastroesophageal Junction	eqtl	3.8e-04	-0.26	6:41716907:A:C
Adipose Visceral Omentum	eqtl	4.6e-04	+0.17	6:41735241:C:T
Artery Aorta	eqtl	5.2e-04	-0.33	6:41738891:T:C
Colon Sigmoid	eqtl	2.0e-03	-0.31	6:41735142:C:T
Esophagus Mucosa	eqtl	2.2e-03	-0.14	6:41735303:G:A
Artery Tibial	eqtl	2.3e-03	-0.23	6:41738891:T:C
Thyroid	eqtl	3.0e-03	-0.17	6:42015657:C:T
Whole Blood	eqtl	3.6e-03	+0.07	6:41721252:T:C
Adipose Subcutaneous	eqtl	4.9e-03	-0.30	6:41738891:T:C
Lung	eqtl	1.1e-02	-0.26	6:41733120:T:C
Pituitary	eqtl	1.1e-02	-0.76	6:41403004:A:G
Pancreas	eqtl	2.0e-02	+0.28	6:41698327:G:A
Skin Not Sun Exposed Suprapubic	eqtl	2.7e-02	-0.45	6:41985558:A:G

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
73556	5.0086	1438
73554	0.4569	218
73553	0.4171	220
73551	0.2769	133
73555	0.2166	92
73550	0.2085	100
73557	0.1913	71
73552	0.1618	65

Top tissues by expression

showing 100 of 296 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	95.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.65	gold quality
gastrocnemius	UBERON:0001388	94.43	gold quality
apex of heart	UBERON:0002098	94.21	gold quality
olfactory bulb	UBERON:0002264	94.04	gold quality
granulocyte	CL:0000094	93.75	gold quality
blood	UBERON:0000178	93.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.39	gold quality
muscle of leg	UBERON:0001383	93.34	gold quality
inferior olivary complex	UBERON:0002127	92.47	gold quality
spinal cord	UBERON:0002240	92.31	gold quality
muscle organ	UBERON:0001630	92.01	gold quality
spleen	UBERON:0002106	91.94	gold quality
inferior vagus X ganglion	UBERON:0005363	91.14	gold quality
leukocyte	CL:0000738	90.84	gold quality
monocyte	CL:0000576	90.74	gold quality
parotid gland	UBERON:0001831	90.72	gold quality
mononuclear cell	CL:0000842	90.69	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.35	gold quality
skeletal muscle tissue	UBERON:0001134	89.96	gold quality
adenohypophysis	UBERON:0002196	89.93	gold quality
lymph node	UBERON:0000029	89.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.63	gold quality
vena cava	UBERON:0004087	89.61	gold quality
cranial nerve II	UBERON:0000941	89.60	gold quality
heart left ventricle	UBERON:0002084	89.58	gold quality
endothelial cell	CL:0000115	89.53	gold quality
cardiac ventricle	UBERON:0002082	89.38	gold quality
pituitary gland	UBERON:0000007	89.30	gold quality
subthalamic nucleus	UBERON:0001906	89.14	gold quality
right atrium auricular region	UBERON:0006631	88.67	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.26	gold quality
lower esophagus	UBERON:0013473	88.22	gold quality
muscle tissue	UBERON:0002385	88.19	gold quality
cardiac atrium	UBERON:0002081	88.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.95	gold quality
vastus lateralis	UBERON:0001379	87.86	gold quality
tongue squamous epithelium	UBERON:0006919	87.82	gold quality
quadriceps femoris	UBERON:0001377	87.73	gold quality
cervix squamous epithelium	UBERON:0006922	87.55	gold quality
heart	UBERON:0000948	87.49	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.42	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.38	gold quality
substantia nigra	UBERON:0002038	87.22	gold quality
triceps brachii	UBERON:0001509	87.21	gold quality
midbrain	UBERON:0001891	87.21	gold quality
biceps brachii	UBERON:0001507	87.11	gold quality
ventral tegmental area	UBERON:0002691	87.08	gold quality
mucosa of transverse colon	UBERON:0004991	87.02	gold quality
left lobe of thyroid gland	UBERON:0001120	86.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.69	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	86.59	gold quality
caecum	UBERON:0001153	86.49	gold quality
nasal cavity mucosa	UBERON:0001826	86.44	gold quality
right lobe of thyroid gland	UBERON:0001119	86.36	gold quality
vermiform appendix	UBERON:0001154	86.33	gold quality
medulla oblongata	UBERON:0001896	86.31	gold quality
putamen	UBERON:0001874	86.21	gold quality
nasal cavity epithelium	UBERON:0005384	86.17	gold quality
tongue	UBERON:0001723	86.13	gold quality
body of tongue	UBERON:0011876	86.11	gold quality
thyroid gland	UBERON:0002046	86.09	gold quality
saliva-secreting gland	UBERON:0001044	86.03	gold quality
gluteal muscle	UBERON:0002000	85.98	gold quality
tibial nerve	UBERON:0001323	85.94	gold quality
superior surface of tongue	UBERON:0007371	85.94	gold quality
right coronary artery	UBERON:0001625	85.75	gold quality
lateral globus pallidus	UBERON:0002476	85.49	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.46	gold quality
amygdala	UBERON:0001876	85.35	gold quality
minor salivary gland	UBERON:0001830	85.34	gold quality
small intestine	UBERON:0002108	85.34	gold quality
lower esophagus mucosa	UBERON:0035834	85.17	gold quality
hair follicle	UBERON:0002073	85.12	gold quality
cardia of stomach	UBERON:0001162	85.11	gold quality
sigmoid colon	UBERON:0001159	85.08	gold quality
transverse colon	UBERON:0001157	85.07	gold quality
popliteal artery	UBERON:0002250	85.02	gold quality
tibial artery	UBERON:0007610	85.00	gold quality
deltoid	UBERON:0001476	84.94	gold quality
placenta	UBERON:0001987	84.93	gold quality
tonsil	UBERON:0002372	84.92	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.88	gold quality
descending thoracic aorta	UBERON:0002345	84.81	gold quality
metanephros cortex	UBERON:0010533	84.67	gold quality
aorta	UBERON:0000947	84.64	gold quality
esophagus	UBERON:0001043	84.64	gold quality
mucosa of stomach	UBERON:0001199	84.58	gold quality
Ammon’s horn	UBERON:0001954	84.58	gold quality
mouth mucosa	UBERON:0003729	84.48	gold quality
diaphragm	UBERON:0001103	84.31	silver quality
nipple	UBERON:0002030	84.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.22	gold quality
ascending aorta	UBERON:0001496	84.19	gold quality
thoracic aorta	UBERON:0001515	84.19	gold quality
pharyngeal mucosa	UBERON:0000355	83.99	gold quality
colon	UBERON:0001155	83.99	gold quality
adult mammalian kidney	UBERON:0000082	83.96	gold quality
skin of leg	UBERON:0001511	83.88	gold quality
upper lobe of left lung	UBERON:0008952	83.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.99

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Skeletal muscle	tissue	53.1
Corpus callosum	tissue	52.6
Tongue	tissue	38.7
Spinal cord	tissue	36.5
Medulla oblongata	tissue	32.9
Substantia nigra	tissue	29.1
Midbrain	tissue	28.2
Nucleus accumbens	tissue	25.2
Lymph node	tissue	24.5
Superior colliculi	tissue	24.1
Hippocampus	tissue	23.7
Periaqueductal gray	tissue	23.7
Thalamus	tissue	23.0
Locus coeruleus	tissue	22.9
Pons	tissue	22.5
Spleen	tissue	21.3
Hypothalamus	tissue	21.0
Putamen	tissue	20.6
Pituitary gland	tissue	19.0
Ventral forebrain	tissue	18.9
Heart muscle	tissue	18.8
Salivary gland	tissue	18.2
Septum	tissue	16.8
Parathyroid gland	tissue	16.7
Hippocampal formation	tissue	16.3
Tonsil	tissue	16.1
Appendix	tissue	15.8
Placenta	tissue	13.7
Postcentral gyrus	tissue	13.6
Choroid plexus	tissue	12.1
Vagina	tissue	11.8
Cerebral cortex	tissue	11.7
Retrosplenial cortex	tissue	11.7
Amygdala	tissue	11.6
Pancreas	tissue	11.1
Somatosensory cortex	tissue	11.1
Basal ganglia	tissue	11.0
Motor cortex	tissue	10.7
Insular cortex	tissue	10.4
Occipital cortex	tissue	10.3
Olfactory bulb	tissue	9.9
Prefrontal cortex	tissue	9.7
Temporal cortex	tissue	9.7
Retrosplenial and cingulate cortex	tissue	9.6
Cerebellum	tissue	9.1
Entorhinal cortex	tissue	8.7
Lung	tissue	8.2
Thyroid gland	tissue	8.0
Adipose tissue	tissue	7.9
Bone marrow	tissue	7.9
Stomach 1	tissue	7.8
Small intestine	tissue	7.3
Gallbladder	tissue	7.3
Prostate	tissue	7.3
Esophagus	tissue	7.2
Urinary bladder	tissue	7.1
Caudate putamen	tissue	6.7
Seminal vesicle	tissue	6.6
Colon	tissue	6.6
Fallopian tube	tissue	6.5

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Temporal white matter (72.9), Parieto-temporal junction (white matter) (72.5), Corpus callosum, splenium (white matter) (59.0), Corpus callosum, genu (white matter) (57.6), Nucleus gracilis (57.6).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets:

Target	Regulation
BEST1	Unknown
CD40LG	Activation
CDH1	Activation
CDH17
CEL
GFAP
H19
LARGE1
SERPINE1	Unknown
TNFRSF11A
TPM1
TYR	Unknown
TYRP1	Unknown

JASPAR motifs

Motif	Name	Family
MA0692.1	TFEB	bHLH-ZIP
MA0692.2	TFEB	bHLH-ZIP

JASPAR matrix evidence (PMIDs): PMID:1748288

miRNA regulators (miRDB)

Targeting TFEB by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 58 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-548AN	99.97	70.91	2817
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4269	99.55	69.89	1373

Functional genomics

gnomAD constraint: pLI 0.995, LOEUF 0.467, missense Z 1.37 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000373033 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:41,684,602–41,684,963	168 / 161.0	1.04	no
6:41,684,964–41,686,171	62 / 90.2	0.69	no
6:41,686,172–41,687,775	28 / 71.9	0.39	no
6:41,687,776–41,691,213	251 / 317.2	0.79	no

Literature-anchored findings (GeneRIF, showing 40)

• This gene fuses with an intronless gene in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. (PMID:12719541)
• TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms (PMID:15644781)
• TFEB in the neoplastic tissue compared to the normal sample, supports that the fusion gene does not encode for a chimeric protein but causes an upregulation of the wild-type TFEB. (PMID:17285572)
• overexpression of TFE3 or TFEB in renal cell carinomas activates the expression of genes normally regulated by microphthalmia transcription factor in other cell types. (PMID:19396149)
• TFEB is identified as a master regulator of lysosomal biogenesis and function. (PMID:19556463)
• study found that starvation activates a transcriptional program controlling major steps of the autophagic pathway; TFEB, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes (PMID:21617040)
• TFEB coordinates the expression of 471 genes network involved in the early and late steps of lysosomal biogenesis. (PMID:21752829)
• TFEB transcriptionally regulates lysosomal exocytosis both by inducing the release of intracellular Ca2+ through its target gene MCOLN1 and by increasing the population of lysosomes ready to fuse with the plasma membrane. (PMID:21889421)
• mTORC1 regulates the nuclear localization of TFEB by promoting phosphorylation in the serine-rich motif. (PMID:22101272)
• When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. (PMID:22343943)
• Describes the clinical and histopathologic features of TFE3 and TFEB translocation renal cell carcinoma. (PMID:22446944)
• Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/MTORC1 complex. (PMID:22576015)
• The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. (PMID:22692423)
• TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease. (PMID:22786682)
• TFEB gene transfer is a novel strategy for treatment of liver disease of alpha-1-anti-trypsin deficiency. (PMID:23381957)
• findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs. (PMID:23393155)
• lysosomal exocytosis induced by TFEB nuclear translocation is required not only for plasma membrane repair and lysosomal content secretion, but also for the recruitment of glycohydrolases on the cell surface. (PMID:24055709)
• HPbetaCD administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system (PMID:24558044)
• Review of the role of gene fusions involving TFE3 and TFEB in carcinogenesis in sporadic renal cell carcinoma. (PMID:25048860)
• We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between TFEB and AR in spinal and bulbar muscular atrophy. (PMID:25108912)
• Results showed the amplification of TFEB locus was found only in the aggressive t(6;11) Renal Cell Carcinoma. (PMID:25438924)
• Data show that drug-induced TFEB-associated lysosomal biogenesis is a determinant of multidrug resistance (MDR) and suggest that circumvention of lysosomal drug sequestration is a strategy to overcome chemoresistance. (PMID:25544758)
• Lysosomal calcium signaling regulates autophagy through calcineurin and TFEB. (PMID:25720963)
• TFEB modulates autophagic clearance of alpha-syn (PMID:25790376)
• RIP1 represses basal autophagy in part due to its ability to regulate the TFEB transcription factor;RIP1 activates ERK, which negatively regulates TFEB though phosphorylation of serine 142 (PMID:25908842)
• a virus modulating TFEB localization and helps to explain how HIV modulates autophagy to promote its own replication and cell survival (PMID:26115100)
• TFEB was found to regulate MuRF1 expression in Angiotensin II-induced skeletal muscle atrophy. (PMID:26137861)
• during mitophagy TFEB translocates to the nucleus and displays transcriptional activity in a PINK1- and Parkin-dependent manner. (PMID:26240184)
• Silencing of TFEB with siRNAs in lung cancer cell lines resulted in reduced migration ability. (PMID:26264650)
• TFEB1 overexpression is associated with drug resistance of ovarian cancer. (PMID:26307679)
• This study demonstrated that transcription factor EB (TFEB) regulate the lysosome biogenesis in neurons of APP/PS1 mice, steady-state levels of APP were reduced, resulting in decreased interstitial fluid Abeta levels and attenuated amyloid deposits (PMID:26338325)
• The autophagic response to polystyrene nanoparticles is mediated by TFEB and depends on surface charge. (PMID:26596266)
• TFEB and TFE3 are novel components of the integrated stress response (PMID:26813791)
• Lack of cystinosin reduced TFEB expression and induced TFEB nuclear translocation. (PMID:26994576)
• TFEB and TFE3 collaborate with each other in activated macrophages and microglia to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of numerous proinflammatory cytokines (PMID:27171064)
• TFEB is affected by a novel curcumin analog in vitro and in vivo independent of MTOR inhibition (PMID:27172265)
• the central autophagy regulator TFEB is expressed and active in PDAC, but autophagy is sustained after TFEB knockdown, suggesting alternative bypass signaling. TFEB is dispensable for gemcitabine-induced cell death, but inversely correlated with KRAS expression. (PMID:27175909)
• Neuronal C-ETS2 senses oxidative stress, activates TFEB transcription, and mediates the upregulation of lysosomal genes. (PMID:27195074)
• Overexpression of deacetylated transcription factor EB at K116R mutant in microglia accelerated intracellular fibrillar Amyloid beta-peptide degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain. (PMID:27209302)
• TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of murine models of disease, such as Parkinson’s and Alzheimer’s, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. (PMID:27252382)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfeb	ENSDARG00000010794
mus_musculus	Tfeb	ENSMUSG00000023990
rattus_norvegicus	Tfeb	ENSRNOG00000014666
drosophila_melanogaster	Mitf	FBGN0263112
caenorhabditis_elegans		WBGENE00020930

Paralogs (3): TFE3 (ENSG00000068323), TFEC (ENSG00000105967), MITF (ENSG00000187098)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103270) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 12 distinct phenotype terms.

Mouse phenotype (MP)	Records
trunk curl	1
abnormal placenta morphology	1
prenatal lethality	1
decreased hemoglobin content	1
decreased circulating alkaline phosphatase level	1
increased lean body mass	1
decreased lean body mass	1
increased susceptibility to bacterial infection induced morbidity/mortality	1
increased total body fat amount	1
preweaning lethality, complete penetrance	1
abnormal eye posterior chamber depth	1
embryonic lethality prior to tooth bud stage	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo pygmaeus	A2T7L8	100.0%	Diamond
Pan troglodytes	A2T713	99.4%	Diamond
Bos taurus	Q05B92	92.9%	Diamond
Psilocybe cyanescens	A0A286LEZ9	81.4%	Diamond
Psilocybe cubensis	P0DPB0	81.4%	Diamond
Gallus gallus	Q5XFQ6	70.3%	Diamond
Schizosaccharomyces pombe 972h-	Q9UUD1	57.4%	Diamond
Saccharomyces cerevisiae S288C	P38165	46.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR4641	ncRNA	100616178
MIR10398	ncRNA	113218489
FOXP4	protein-coding	116113
MDFI	protein-coding	4188
PGC	protein-coding	5225
TOMM6	protein-coding	100188893
PRICKLE4	protein-coding	29964
FRS3	protein-coding	10817
FOXP4-AS1	ncRNA	101060264

Protein

Protein identifiers

Transcription factor EB — P19484 (reviewed: P19484)

Alternative names: Class E basic helix-loop-helix protein 35

All UniProt accessions (11): P19484, A0A1B0GXL9, A0A7I2YQR9, B0QYS6, B0QYS7, B1AKA9, B1AKB1, B1AKB2, B1AKB4, B1AKB5, Q709A9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response. Specifically recognizes and binds E-box sequences (5’-CANNTG-3’); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF. Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation. Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity. Specifically recognizes and binds the CLEAR-box sequence (5’-GTCACGTGAC-3’) present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes. Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1. Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy. In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity. Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer. Plays a role in the signal transduction processes required for normal vascularization of the placenta. Involved in the immune response to infection by the bacteria S.aureus, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity. Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response. In association with ACSS2, promotes the expression of genes involved in lysosome biogenesis and both autophagy upon glucose deprivation.

Subunit / interactions. Homodimer and heterodimer; with TFE3 or MITF. Interacts (when phosphorylated by MTOR) with YWHAZ; promoting retention in the cytosol. Interacts with IRGM; promoting association between TFEB and PPP3CB and dephosphorylation. Interacts with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD); promoting its recruitment to lysosomal membrane in the presence of nutrients. Interacts with ACSS2.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Lysosome membrane Nucleus.

Post-translational modifications. Phosphorylation at Ser-211 by MTOR via non-canonical mTORC1 pathway regulates its subcellular location and activity. When nutrients are present, phosphorylation by MTOR promotes association with 14-3-3/YWHA adapters and retention in the cytosol. Inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation by calcineurin PPP3CB and translocation to the nucleus. Dephosphorylated by calcineurin PPP3CB in response to lysosomal Ca(2+) release. IRGM promotes dephosphorylation by calcineurin PPP3CB, resulting in TFEB nuclear translocation and stimulation of lysosomal biogenesis. Dephosphorylated by phosphatase PPP3CA following Coxsackievirus B3 infection, leading to nuclear translocation. Exported from the nucleus in a mTORC1-dependent manner in response to nutrient availability. Alkylated via a non-enzymatic covalent modification. Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates Cys-212, preventing association with 14-3-3/YWHA adapters, thereby promoting nuclear translocation and activity. Sumoylated; does not affect dimerization with MITF. (Microbial infection) Cleavage by Coxsackievirus B3 protease 3C after site Gln-60. This non-phosphorylated cleavage product retains its ability to interact with TFEB, TFE3 or MITF and presents impaired transcriptional activity, resulting in disruption of lysosomal functions and increased viral infection.

Activity regulation. Inhibited by eltrombopag drug, which binds to the bHLH domain and disrupts DNA-binding.

Domain organisation. The leucine zipper region is essential for homo- or heterodimerization and high-affinity DNA binding. DNA binding is mediated by the basic region.

Similarity. Belongs to the MiT/TFE family.

Isoforms (2)

UniProt ID	Names	Canonical?
P19484-1	1	yes
P19484-2	2

RefSeq proteins (5): NP_001161299, NP_001258872, NP_001258873, NP_001258874, NP_009093 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR021802	MiT/TFE_C	Domain
IPR024098	bHLHzip_TFEB	Domain
IPR031867	MiT/TFE_N	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010, PF11851, PF15951

UniProt features (72 total): mutagenesis site 24, modified residue 14, helix 10, region of interest 7, compositionally biased region 4, sequence conflict 3, short sequence motif 2, strand 2, turn 2, chain 1, domain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
7Y62	Crystal structure of human TFEB HLHLZ domain	X-RAY DIFFRACTION	2
7UX2	cryo-EM structure of the Raptor-TFEB-Rag-Ragulator complex	ELECTRON MICROSCOPY	2.9
7UXC	cryo-EM structure of the mTORC1-TFEB-Rag-Ragulator complex with symmetry expansion	ELECTRON MICROSCOPY	3.2
7UXH	cryo-EM structure of the mTORC1-TFEB-Rag-Ragulator complex	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19484-F1	64.95	0.25

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains, Cancer-related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IF supported

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 (1)

Position	Role
60–61	(microbial infection) cleavage; by coxsackievirus b3 protease 3c

Post-translational modifications (14)

Type	Positions
Phosphoserine	109, 114, 122, 138, 142, 211, 332, 423, 441, 466, 467, 469
Phosphothreonine	183
S-(2,3-dicarboxypropyl)cysteine	212

Mutagenesis-validated functional residues (24)

Position	Phenotype
3–4	abolished recruitment to lysosomal membrane in response to nutrients, leading to constitutive nuclear localization.
10–11	abolished recruitment to lysosomal membrane in response to nutrients, leading to constitutive nuclear localization.
19–20	does not affect recruitment to lysosomal membrane in response to nutrients.
22–24	does not affect recruitment to lysosomal membrane in response to nutrients.
60–61	impaired cleavage by coxsackievirus b3 protease 3c.
138	impaired nuclear export in response to nutrient availability.
142	impaired phosphorylation by mtor, leading to constitutive nuclear localization and transcription factor activity. impaired nuclear export …
142	mimics phosphorylation status; abolished translocation to the nucleus in response to starvation.
144–149	abolished nuclear export in response to nutrient availability.
209	does not affect interaction with 14-3-3/ywha and subcellular localization.
210	does not affect interaction with 14-3-3/ywha and subcellular localization.
211	impaired phosphorylation by mtor, leading to reduced interaction with 14-3-3/ywha and constitutive nuclear localization. does not affect …
211	mimics phosphorylation; leading to increased interaction with 14-3-3/ywha and impaired nuclear localization.
212	abolished alkylation, abolishing ability to prevent association with 14-3-3/ywha adapters.
245–247	abolished nuclear localization upon mtorc1 inactivation.
248–254	in mutcom_1 mutant; abolished ability to bind eltrombopag drug; when associated with 271-a–a-274.
256–264	in mutcom_2 mutant; does not affect ability to bind eltrombopag drug.
271–274	in mutcom_1 mutant; abolished ability to bind eltrombopag drug; when associated with 248-a–a-254.
271	abolished ability to bind eltrombopag drug.
279–290	in mutcom_3 mutant; does not affect ability to bind eltrombopag drug.
296–315	in mutcom_4 mutant; does not affect ability to bind eltrombopag drug.
331–332	does not affect interaction with 14-3-3/ywha and subcellular localization.
332	does not affect nuclear localization.
423	does not affect nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-9909396	Circadian clock	—
R-HSA-1266738	Developmental Biology	—
R-HSA-9730414	MITF-M-regulated melanocyte development	—
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	electronic
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity	electronic

MSigDB gene sets: 266 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_AUTOPHAGY, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, BOHN_PRIMARY_IMMUNODEFICIENCY_SYNDROM_DN, GTGCCTT_MIR506, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, RICKMAN_METASTASIS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (18): embryonic placenta development (GO:0001892), adaptive immune response (GO:0002250), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), autophagy (GO:0006914), humoral immune response (GO:0006959), lysosome organization (GO:0007040), cellular response to starvation (GO:0009267), positive regulation of autophagy (GO:0010508), lysosome localization (GO:0032418), cellular response to amino acid starvation (GO:0034198), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to Gram-negative bacterium (GO:0050829), antibacterial innate immune response (GO:0140367), regulation of lysosome organization (GO:1905671), immune system process (GO:0002376)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), enzyme binding (GO:0019899), protein heterodimerization activity (GO:0046982), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829)

Reactome top-level categories

3 top-level categories:

Category	Pathways
MITF-M-regulated melanocyte development	1
Circadian clock	1
Developmental Biology	1

GO top-level categories

57 GO namespaces:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
immune response	2
DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
defense response to bacterium	2
protein binding	2
in utero embryonic development	1
placenta development	1
embryonic organ development	1
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
lytic vacuole organization	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
vacuolar localization	1
cellular response to starvation	1
response to amino acid starvation	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
innate immune response	1
lysosome organization	1
regulation of vacuole organization	1
biological_process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
protein dimerization activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 35 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
antibacterial innate immune response	BP	direct assay
cellular response to amino acid starvation	BP	direct assay
cellular response to starvation	BP	direct assay
lysosome localization	BP	mutant phenotype
lysosome organization	BP	direct assay
positive regulation of DNA-templated transcription	BP	direct assay
positive regulation of autophagy	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of lysosome organization	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
lysosomal membrane	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription factor activity	MF	direct assay
enzyme binding	MF	physical interaction
sequence-specific double-stranded DNA binding	MF	direct assay
transcription cis-regulatory region binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,550 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFEB	MCOLN1	Q9GZU1	839
TFEB	ULK1	O75385	838
TFEB	MTOR	P42345	837
TFEB	LAMP1	P11279	816
TFEB	BECN1	Q14457	809
TFEB	LAMP2	P13473	786
TFEB	ATG7	O95352	772
TFEB	ATG5	Q9H1Y0	760
TFEB	CTSB	P07858	751
TFEB	SQSTM1	Q13501	747
TFEB	CTSK	P43235	735
TFEB	CTSD	P07339	712
TFEB	ATG13	O75143	709
TFEB	MAP1LC3B	Q9GZQ8	697
TFEB	UVRAG	Q9P2Y5	656

IntAct

Human interaction partners of TFEB in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAE	physical association	0.740	1
MITF	association	0.560	4
MTOR	phosphorylation reaction	0.440	1
SRPK1	phosphorylation reaction	0.440	1
SUMO1	physical association	0.400	2
PPP3CB	physical association	0.400	1
CFTR	physical association	0.370	1
TFEC	association	0.350	2
PPM1G	association	0.350	1

BioGRID (66 interactions; top human partners by supporting records): MITF (Affinity Capture-MS; 4 records), TFE3 (Affinity Capture-MS; 4 records), YWHAB (Affinity Capture-MS; 3 records), YWHAE (Affinity Capture-MS; 3 records), YWHAG (Affinity Capture-MS; 3 records), FBXL5 (Affinity Capture-Western; 2 records), HDAC5 (Affinity Capture-Western; 2 records), RRAGA (Affinity Capture-Western; 2 records), STUB1 (Affinity Capture-Western; 2 records), TAF9 (Affinity Capture-MS; 2 records), TFEC (Affinity Capture-MS; 2 records), TRIM16 (Affinity Capture-Western; 2 records), YWHAQ (Affinity Capture-MS; 2 records), YWHAZ (Affinity Capture-MS; 2 records), ANXA2 (Affinity Capture-Western)

SIGNOR signaling

showing 54 of 76 signaling interactions:

A	Effect	B	Mechanism
MTOR	“down-regulates activity”	TFEB	phosphorylation
mTORC1	“down-regulates activity”	TFEB	phosphorylation
MAPK1	“down-regulates activity”	TFEB	phosphorylation
PPP3CB	“up-regulates activity”	TFEB	dephosphorylation
MAP4K3	“down-regulates activity”	TFEB	phosphorylation
CDK4	“up-regulates activity”	TFEB	phosphorylation
CDK6	“up-regulates activity”	TFEB	phosphorylation
ABL1	“down-regulates activity”	TFEB	phosphorylation
PRKCB	“up-regulates activity”	TFEB	phosphorylation
TFEB	“up-regulates quantity by expression”	ATP6V0E1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	ATP6V1H	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CLCN7	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GALNS	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GLA	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GNS	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	HEXA	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	LAMP1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NAGLU	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NEU1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PSAP	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	SGSH	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PIP4P1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	TPP1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CTSA	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GBA	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GUSB	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PPM1D	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	BECN1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	MAP1LC3B	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	BLOC1S2	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	BLOC1S3	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFA1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFA13	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFA8	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFAF2	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFB10	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	NDUFS4	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PPARA	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PPARG	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PPARGC1A	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	ACACB	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	ACOT2	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	ANKFY1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	APOA4	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CALCOCO1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CD36	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CYP17A1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	CYP7A1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	DRAM1	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	PPP1R15A	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	FABP3	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	FGF21	“transcriptional regulation”
TFEB	“up-regulates quantity by expression”	GOLPH3L	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ mTORC1-TFEB-Rag-Ragulator complex	11	LAMTOR2, LAMTOR4, LAMTOR5, RPTOR, RRAGC, LAMTOR1, LAMTOR3, MLST8, MTOR, RRAGA, TFEB

Disease & clinical

Genetic variants

Variant evidence for TFEB: 42 ClinVar records (0 pathogenic / likely pathogenic); 14 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 20 predictions of 927):

Position(s)	Effect	Δscore	Sites
6:41686238–41686239	acceptor_loss	1.0000	2
6:41686245	acceptor_gain	1.0000
6:41686248	acceptor_gain	1.0000
6:41687752	donor_loss	1.0000	2
6:41687756	donor_gain	1.0000
6:41687818–41687819	acceptor_gain	1.0000	2
6:41687906–41687907	donor_loss	1.0000	3
6:41688029–41688030	acceptor_loss	1.0000	6
6:41688031	acceptor_gain	1.0000
6:41688036	acceptor_gain	1.0000

AlphaMissense

982 missense substitutions predicted likely pathogenic (of 3,135 scored), across 232 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M12	9	0.928	0.995
H240	8	1.000	1.000
N241	8	0.999	1.000
N252	8	0.999	1.000
N273	8	0.999	1.000
D238	8	0.996	0.999
D253	8	0.992	0.999
N250	8	0.988	1.000
N239	8	0.957	0.999
F249	8	0.955	1.000
S142	8	0.897	0.997
D269	8	0.893	0.977
D267	8	0.876	0.962
H326	8	0.846	0.989
D291	8	0.836	0.965
D448	8	0.737	0.834
E244	7	1.000	1.000
R248	7	1.000	1.000
I251	7	0.999	1.000
I255	7	0.999	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.93e-08
Breast Invasive Carcinoma (TCGA)	favorable	0.000905

Disease associations

OMIM: gene MIM:600744 | disease phenotypes:

GWAS associations

14 associations:

Study	Trait	p-value
GCST008058_71	Estimated glomerular filtration rate	3e-20
GCST008059_57	Estimated glomerular filtration rate	1e-15
GCST010321_198	PR interval	2e-12
GCST90002407_127	White blood cell count	2e-12
GCST010320_23	PR interval	2e-11
GCST008747_152	Estimated glomerular filtration rate	5e-11
GCST005985_22	Creatinine levels	1e-8
GCST003799_2	Colorectal cancer	4e-8
GCST007876_146	Estimated glomerular filtration rate	4e-8
GCST008745_45	Estimated glomerular filtration rate in non-diabetics	4e-8
GCST000246_16	Attention deficit hyperactivity disorder	3e-6
GCST003815_45	Late-onset Alzheimer’s disease	5e-6
GCST007552_2	Colorectal cancer	6e-6
GCST008062_93	Blood urea nitrogen levels	6e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease
EFO:0004462	PR interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067602 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Go-Y019	EC50	3300 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.66	EC50	2167	nM	CHEMBL477053

PubChem BioAssay actives

1 with measured affinity, of 1 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
(1E,4E)-1,5-bis(2-methoxyphenyl)penta-1,4-dien-3-one	2138367: Binding affinity to full length N-terminal his6-tagged human TFEB expressed in Escherichia coli by isothermal titration calorimetry analysis	ec50	2.1670	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases phosphorylation, decreases reaction, affects cotreatment, increases reaction, increases expression (+3 more)	5
Acetylcysteine	decreases reaction, increases expression, affects localization, decreases phosphorylation	4
Sirolimus	decreases expression, decreases reaction, increases phosphorylation, increases expression, affects localization	3
4-(4-fluorophenyl)sulfonyl-5-methylthio-2-phenyloxazole	affects localization, decreases phosphorylation, affects cotreatment, decreases reaction, affects reaction (+1 more)	2
nuciferine	decreases reaction, affects binding, increases localization, affects localization	2
apilimod	affects localization, decreases phosphorylation, affects response to substance, increases response to substance	2
dorsomorphin	increases expression, affects localization, decreases reaction, affects cotreatment	2
alpha-Chlorohydrin	decreases expression, affects cotreatment, affects localization, decreases reaction, increases expression	2
Cyclosporine	affects cotreatment, affects localization, decreases reaction, decreases expression	2
Okadaic Acid	decreases phosphorylation, decreases reaction, decreases expression	2
aristolochic acid I	increases expression	1
APY0201	affects localization, decreases phosphorylation, increases activity, increases response to substance	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression, decreases reaction	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	affects localization, decreases reaction, decreases phosphorylation, affects reaction, increases expression (+1 more)	1
oligomycin A	affects cotreatment, affects localization, affects reaction, affects expression, affects response to substance	1
betadex	affects localization	1
leucyl-leucine-methyl ester	affects localization, increases expression, increases reaction	1
epigallocatechin gallate	affects localization, increases expression, affects reaction, decreases expression	1
bafilomycin A	affects reaction, increases lipidation	1
tamibarotene	increases expression	1
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	affects localization, decreases reaction	1
1-acyl-2-(12-((7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)dodecanoyl)phosphatidylcholine	decreases reaction, increases import	1
entinostat	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5628396	Binding	Binding affinity to full length N-terminal his6-tagged human TFEB expressed in Escherichia coli by isothermal titration calorimetry analysis	Targeting autophagy with small-molecule activators for potential therapeutic purposes. — *Eur J Med Chem*

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0ZS	Abcam Hep-G2 TFEB KO	Cancer cell line	Male
CVCL_C3IN	HeLa-TFEB	Cancer cell line	Female
CVCL_C3IP	HeLa-TFEB-3xFLAG	Cancer cell line	Female
CVCL_E0X7	Ubigene L-02 TFEB KO	Cancer cell line	Female
CVCL_E1GF	Abcam Raji TFEB KO	Cancer cell line	Male
CVCL_F4MR	HyCyte HT22 stable cell line for hTFEB overexpression	Transformed cell line
CVCL_F4Q0	HyCyte HMC3 stable cell line for hTFEB overexpression	Transformed cell line	Sex unspecified
CVCL_TS18	HAP1 TFEB (-) 1	Cancer cell line	Male
CVCL_TS19	HAP1 TFEB (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TFEB across ~30M SureChEMBL compounds — explore on Sugi Predict.