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 positive regulation of metabolic process. Located in cytosol and lysosomal membrane. Is active in nucleus.

Source: NCBI Gene 7942 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_001271944

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: 43 — 39 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000230323, ENST00000343317, ENST00000358871, ENST00000373033, 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

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.

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

296 total, 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

Single-cell (SCXA)

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

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

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)

58 targeting TFEB, 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-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

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)

Protein

Protein identifiers

Transcription factor EB — P19484 (reviewed: P19484)

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

All UniProt accessions (11): A0A1B0GXL9, A0A7I2YQR9, B0QYS6, B0QYS7, B1AKA9, B1AKB1, B1AKB2, B1AKB4, B1AKB5, P19484, 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 (70 total): mutagenesis site 24, modified residue 14, helix 8, 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.

PDB	Method	Resolution (Å)
7Y62	X-RAY DIFFRACTION	2
7UX2	ELECTRON MICROSCOPY	2.9
7UXC	ELECTRON MICROSCOPY	3.2
7UXH	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

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

Functional residue map

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

Catalytic / active sites (1): 60–61 ((microbial infection) cleavage; by coxsackievirus b3 protease 3c)

Post-translational modifications (14): 109, 114, 122, 138, 142, 183, 211, 212, 332, 423, 441, 466, 467, 469

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. impair
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.
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

4 pathways

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

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 (17): embryonic placenta development (GO:0001892), adaptive immune response (GO:0002250), 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 (8): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	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
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

Protein interactions and networks

STRING

2630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFEB	MCOLN1	Q9GZU1	856
TFEB	MTOR	P42345	839
TFEB	PRCC	Q92733	820
TFEB	ATG13	O75143	820
TFEB	BECN1	Q14457	782
TFEB	LAMP1	P11279	770
TFEB	ATG5	Q9H1Y0	762
TFEB	ATG7	O95352	756
TFEB	CTSK	P43235	753
TFEB	SQSTM1	Q13501	743
TFEB	RRAGC	Q9HB90	731
TFEB	CTSD	P07339	726
TFEB	MAP1LC3B	Q9GZQ8	717
TFEB	RRAGA	Q7L523	713
TFEB	FOXO1	Q12778	708

IntAct

27 interactions, top by confidence:

A	B	Type	Score
YWHAE	TFEB	psi-mi:“MI:0915”(physical association)	0.740
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
MITF	TFEB	psi-mi:“MI:0915”(physical association)	0.560
MITF	TFEB	psi-mi:“MI:0914”(association)	0.560
TFEB	MITF	psi-mi:“MI:0914”(association)	0.560
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SRPK1	TFEB	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MTOR	TFEB	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
TFEB	PPP3CB	psi-mi:“MI:0915”(physical association)	0.400
TFEB	SUMO1	psi-mi:“MI:0915”(physical association)	0.400
TFEB	CFTR	psi-mi:“MI:0915”(physical association)	0.370
TFEB	PPM1G	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
TFEB	TFEC	psi-mi:“MI:0914”(association)	0.350
MITF	TFEB	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
YWHAQ	FOXO6	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	TFEB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (65): TFEB (Affinity Capture-MS), ATP5J (Affinity Capture-MS), IFIT1 (Affinity Capture-MS), STT3A (Affinity Capture-MS), MAPT (Affinity Capture-MS), MITF (Affinity Capture-MS), PPM1G (Affinity Capture-MS), TFE3 (Affinity Capture-MS), BAG2 (Affinity Capture-MS), C10orf12 (Affinity Capture-MS), MCAT (Affinity Capture-MS), EML4 (Affinity Capture-MS), TBC1D14 (Affinity Capture-MS), HDAC5 (Affinity Capture-Western), TFEB (Affinity Capture-Western)

ESM2 similar proteins: A0A8C0NGY6, A0A8I3PQN6, A1L1N5, A2BEA6, A2ICN5, A2VDZ3, A4QNP0, D6C652, F1LYL9, H2LBU8, O18896, O94842, P19484, P23899, P27889, P35680, P46936, P46937, P46938, P48436, P61753, P61754, Q02078, Q03365, Q04887, Q0P5K4, Q1L8J7, Q2EJA0, Q2LE08, Q2MJT0, Q32NJ6, Q4VYR7, Q571K4, Q5R6A9, Q5RER5, Q5XGD9, Q62431, Q6GQD7, Q7YRJ7, Q7ZXH3

Diamond homologs: A0A286LEZ9, A2T713, A2T7L8, A4IFU7, O02818, O14948, O75030, O88368, P0DPB0, P17106, P19484, P19532, P22415, P49379, Q05B92, Q07957, Q08874, Q10186, Q5A1E3, Q5XFQ6, Q61069, Q63302, Q64092, Q6XBT4, Q9R210, Q9WTW4, H2KZZ2, P38165, A3KNA7, O43019, O97676, P36956, P56720, Q12772, Q3T1I5, Q3U1N2, Q4WIN1, Q59RL7, Q60416, Q60429

SIGNOR signaling

76 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”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
Activation of BAD and translocation to mitochondria	6	253.8×	2e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	223.9×	3e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	223.9×	3e-12
Activation of BH3-only proteins	6	165.5×	2e-11
RHO GTPases activate PKNs	6	105.7×	3e-10
Intrinsic Pathway for Apoptosis	6	97.6×	4e-10
Transcriptional and post-translational regulation of MITF-M expression and activity	8	79.3×	2e-12
SARS-CoV-1-host interactions	6	58.6×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	91.6×	5e-07
intracellular protein localization	6	31.4×	3e-06

Disease & clinical

Cancer significance

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1799 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41686235:TCC:T	acceptor_gain	1.0000
6:41686236:CC:C	acceptor_gain	1.0000
6:41686236:CCC:C	acceptor_gain	1.0000
6:41686237:CC:C	acceptor_gain	1.0000
6:41686238:C:CC	acceptor_gain	1.0000
6:41686245:A:T	acceptor_gain	1.0000
6:41686248:A:T	acceptor_gain	1.0000
6:41687092:A:AC	donor_gain	1.0000
6:41687093:C:CC	donor_gain	1.0000
6:41687093:CAGGT:C	donor_gain	1.0000
6:41687165:TTCAA:T	acceptor_gain	1.0000
6:41687167:CAA:C	acceptor_gain	1.0000
6:41687170:C:CC	acceptor_gain	1.0000
6:41687749:TCA:T	donor_loss	1.0000
6:41687750:CACTT:C	donor_loss	1.0000
6:41687751:A:AC	donor_gain	1.0000
6:41687751:ACTTA:A	donor_loss	1.0000
6:41687752:C:CA	donor_gain	1.0000
6:41687752:CT:C	donor_gain	1.0000
6:41687752:CTT:C	donor_gain	1.0000
6:41687752:CTTA:C	donor_gain	1.0000
6:41687755:A:AC	donor_gain	1.0000
6:41687756:A:C	donor_gain	1.0000
6:41687809:TC:T	acceptor_loss	1.0000
6:41687810:C:CA	acceptor_loss	1.0000
6:41687818:C:CT	acceptor_gain	1.0000
6:41687818:C:T	acceptor_gain	1.0000
6:41687819:A:T	acceptor_gain	1.0000
6:41687902:CAGTA:C	donor_loss	1.0000
6:41687903:AGTAC:A	donor_loss	1.0000

AlphaMissense

3135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41685074:A:G	L319P	1.000
6:41686097:C:G	R315P	1.000
6:41686106:A:G	L312P	1.000
6:41686199:G:A	S281F	1.000
6:41686199:G:T	S281Y	1.000
6:41686200:A:G	S281P	1.000
6:41686203:C:G	A280P	1.000
6:41686208:A:C	L278R	1.000
6:41686208:A:G	L278P	1.000
6:41686208:A:T	L278H	1.000
6:41686209:G:A	L278F	1.000
6:41686211:A:C	I277S	1.000
6:41686211:A:G	I277T	1.000
6:41686211:A:T	I277N	1.000
6:41686217:C:A	G275V	1.000
6:41686217:C:G	G275A	1.000
6:41686217:C:T	G275D	1.000
6:41686218:C:A	G275C	1.000
6:41686218:C:G	G275R	1.000
6:41686218:C:T	G275S	1.000
6:41686219:C:A	K274N	1.000
6:41686219:C:G	K274N	1.000
6:41686220:T:A	K274M	1.000
6:41686221:T:C	K274E	1.000
6:41686221:T:G	K274Q	1.000
6:41686222:G:C	N273K	1.000
6:41686222:G:T	N273K	1.000
6:41686223:T:A	N273I	1.000
6:41686224:T:C	N273D	1.000
6:41687115:A:G	L261P	1.000

dbSNP variants (sampled 300 via entrez): RS1000086416 (6:41697274 G>A), RS1000121533 (6:41701465 A>C), RS1000228983 (6:41723696 G>A,C), RS1000281449 (6:41723878 G>C), RS1000286230 (6:41695131 T>C), RS1000299506 (6:41712135 T>C), RS1000360123 (6:41689623 G>A,C), RS1000371186 (6:41696116 A>C), RS1000381486 (6:41700368 A>C), RS1000392626 (6:41689915 C>T), RS1000406544 (6:41729108 C>A), RS1000497509 (6:41701134 C>T), RS1000504601 (6:41684614 C>T), RS1000594867 (6:41723653 C>A,G,T), RS1000615732 (6:41725389 G>T)

Disease associations

OMIM: gene MIM:600744 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000246_16	Attention deficit hyperactivity disorder	3.000000e-06
GCST003799_2	Colorectal cancer	4.000000e-08
GCST003815_115	Late-onset Alzheimer’s disease	5.000000e-06
GCST005985_22	Creatinine levels	1.000000e-08
GCST007552_17	Colorectal cancer	6.000000e-06
GCST007876_25	Estimated glomerular filtration rate	4.000000e-08
GCST008058_96	Estimated glomerular filtration rate	3.000000e-20
GCST008059_14	Estimated glomerular filtration rate	1.000000e-15
GCST008062_107	Blood urea nitrogen levels	6.000000e-06
GCST008745_57	Estimated glomerular filtration rate in non-diabetics	4.000000e-08
GCST008747_56	Estimated glomerular filtration rate	5.000000e-11
GCST010320_147	PR interval	2.000000e-11
GCST010321_23	PR interval	2.000000e-12
GCST90002407_259	White blood cell count	2.000000e-12

EFO canonical traits (2, from GWAS)

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 (VIP=true, CPIC=false)

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, affects reaction (+3 more)	5
Acetylcysteine	decreases reaction, increases expression, affects localization, decreases phosphorylation	4
Sirolimus	affects localization, decreases expression, decreases reaction, increases phosphorylation, increases expression	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 reaction, increases expression, decreases expression, affects cotreatment, affects localization	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	decreases reaction, increases expression	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	decreases phosphorylation, affects reaction, increases expression, affects response to substance, affects localization (+1 more)	1
oligomycin A	affects expression, affects response to substance, affects cotreatment, affects localization, affects reaction	1
betadex	affects localization	1
leucyl-leucine-methyl ester	increases reaction, affects localization, increases expression	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

7 cell lines: 7 cancer 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_TS18	HAP1 TFEB (-) 1	Cancer cell line	Male
CVCL_TS19	HAP1 TFEB (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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