{
 "key": "MITF_TFE",
 "name": "MITF / TFE (CLEAR)",
 "class": "bHLH",
 "aka": [
  "CLEAR box",
  "CLEAR element",
  "M-box",
  "melanocyte M-box",
  "MiT/TFE family site",
  "TCATGTGA",
  "GTCACGTGAC E-box"
 ],
 "definition": "CLEAR/M-box GTCACGTGAC. MITF, TFE3, TFEB, TFEC.",
 "consensus": "GTCACGTGAC",
 "dataConsensus": "gGTCACGTGAt",
 "motifCount": 14,
 "bySource": {
  "JASPAR": 4,
  "HOCOMOCO": 6,
  "CIS-BP": 4
 },
 "symbols": [
  "MITF",
  "TFE3",
  "TFEB",
  "TFEC"
 ],
 "representative": "TFE3.H14CORE.0.PSM.A",
 "cohesion": 0.94,
 "short": "MITF, TFE3, TFEB and TFEC are bHLH-LZ factors that dimerize only with each other, because a three-residue insertion kinks their leucine zipper. They read a canonical E-box core with a preference for T and A flanks, giving the palindromic 10-mer GTCACGTGAC, known as the CLEAR box in lysosomal and autophagy promoters; at the weaker CATGTG form of the core the 5' T is not merely preferred but required, and that version is the melanocyte M-box (TCATGTGA) of the pigmentation genes. MITF is the lineage factor of melanocytes and is mutated in Waardenburg syndrome type 2A and predisposes to melanoma; TFEB and TFE3 run the lysosome-autophagy program downstream of mTORC1 and are recurrently rearranged in renal cell carcinoma. The four paralogues cannot be told apart from sequence.",
 "long": "## The factors\n\nMITF, TFE3, TFEB and TFEC form the MiT/TFE family of basic helix-loop-helix leucine zipper (bHLH-LZ) factors. MITF was identified from the mouse microphthalmia locus, where mutations cause loss of melanocytes, deafness and small eyes [PMID:8343963]; the three TFE genes were then recognized as a discrete family that dimerizes internally - each member homodimerizes and heterodimerizes with the others, but not with MYC, MAX or USF [PMID:7958932]. The structural basis is a three-residue insertion that kinks the leucine zipper, which excludes the other bHLH-ZIP proteins from the dimer interface and explains why MiT/TFE factors, despite reading the same DNA core, form a closed dimerization set [PMID:23207919]. Expression is what separates them: MITF is restricted (melanocytes, mast cells, osteoclasts, retinal pigment epithelium) and has multiple isoforms driven from alternative promoters, TFE3 and TFEB are broadly expressed and act as the general lysosomal-autophagy arm, and TFEC is largely myeloid. All four are regulated post-translationally rather than only transcriptionally; TFEB in particular is phosphorylated by mTORC1 at the lysosomal surface and held in the cytoplasm until nutrient stress releases it [PMID:22692423]. The atlas assigns 14 motifs here (4 JASPAR, 6 HOCOMOCO, 4 CIS-BP) across all four symbols, cohesion 0.94, with TFE3.H14CORE.0.PSM.A as the representative.\n\n## The motif\n\nThe core is the canonical E-box CACGTG, read as two CAC half-sites by the histidine-glutamate-arginine triad in each basic region, exactly as in MAX [PMID:23207919]. What distinguishes MiT/TFE is the flanking base, but the requirement is specific to one form of the core. At a CATGTG E-box a 5' T is essential: MITF bound TCATGTGA and not the same E-box lacking the T, correctly predicting that the CATGTG box of the P gene would not be bound, and the E-boxes of the tyrosinase, TRP-1, TRP-2 and QNR-71 promoters carry the T without exception [PMID:9819381]. That T-flanked CATGTG is the classical melanocyte M-box [PMID:1321344,7958932]. At a CACGTG E-box the same work saw no specific requirement for the flanking sequence [PMID:9819381], even though every MiT/TFE model in these databases is built with a T and the reciprocal A around the core, giving the palindromic 10-mer GTCACGTGAC. In the lysosomal literature that 10-mer is called the CLEAR element (Coordinated Lysosomal Expression And Regulation), GTCACGTGAC, found in the promoters of most lysosomal hydrolase, subunit and trafficking genes [PMID:19556463]. So the M-box and the CLEAR box are one arrangement described in two fields, a T/A-flanked E-box, differing only in the central base pair of the core. Two consequences follow. First, MITF, TFE3, TFEB and TFEC are not separable from one another by sequence: pairwise similarity among their models in this atlas is 0.97-0.995. Second, the motif is essentially identical to the USF motif, and very close to BHLHE41 and CLOCK-BMAL1 models, so the T/A flanks buy discrimination against MYC-MAX but not against those. The family data also contains lower-information, ChIP-derived variants (a grade-C TFEB model reading gTCACATG) that lose the 3' half entirely.\n\n## Where it acts\n\nMiT/TFE sites are promoter-proximal and CpG-island-associated. The CLEAR network was defined as a few hundred coordinately regulated lysosomal and autophagy genes carrying the element within the first few hundred base pairs of the transcription start site [PMID:19556463,21752829], and TFEB ChIP-seq recovers that set plus autophagosome-formation genes [PMID:21752829,21617040]. MITF occupancy is layered on top of a melanocyte-specific accessibility landscape: the same GTCACGTGAC sequence is used at pigmentation genes (TYR, DCT, TYRP1, PMEL), at lysosome-related genes in melanosome biogenesis, and at proliferation genes, and MITF co-occupies melanocyte enhancers with SOX10 and the AP-1 machinery. TFEB and TFE3 occupancy is switched by subcellular localization rather than by motif availability - the sites are present and often accessible even when the factor is cytoplasmic [PMID:19556463,22692423].\n\n## Biology and disease\n\nMITF is the lineage-determining factor of the melanocyte: loss-of-function alleles cause the mouse microphthalmia phenotypes and, in humans, Waardenburg syndrome type 2A (deafness with pigmentary anomalies) [PMID:8343963,7874167] and Tietz syndrome. The recurrent MITF E318K substitution, which impairs SUMOylation, raises melanoma risk and also associates with renal cell carcinoma [PMID:22080950,22012259]. TFEB and TFE3 drive lysosomal biogenesis and autophagy downstream of mTORC1 and starvation [PMID:21617040,22692423], and are involved in lysosomal storage disease biology as therapeutic targets. Translocations involving these genes are diagnostic in cancer: promoter substitution at t(6;11)(p21;q13) drives TFEB overexpression in a distinct renal cell carcinoma subtype, and TFE3 fusions define another renal carcinoma group [PMID:12837690] and alveolar soft part sarcoma.\n\n## Reading a hit\n\nA GTCACGTGAC or TCATGTGA hit identifies a T/A-flanked E-box. That is a real narrowing - it argues against MYC-MAX - but it does not name the factor: USF1/USF2, BHLHE41, CLOCK-BMAL1 and all four MiT/TFE proteins share it. Within the family, a hit cannot distinguish MITF from TFE3, TFEB or TFEC; the usual discriminator is expression, so a hit in melanocyte data suggests MITF and a hit in a starvation experiment suggests TFEB, and neither inference comes from the sequence. ChIP-derived MiT/TFE models are additionally biased toward active CpG-island promoters. Prefer the HOCOMOCO models with in vitro (S or M) support.",
 "caveats": "The T/A flanks make this motif distinguishable from MYC-MAX but not from USF1/USF2, BHLHE41 or CLOCK-BMAL1, which prefer the same extended palindrome; a GTCACGTGAC hit therefore names a group, not a protein. Within the family MITF, TFE3, TFEB and TFEC share one motif at 0.97-0.995 similarity, so assignment relies entirely on which factor is expressed and, for TFEB/TFE3, on whether it is nuclear at the time. Several models here are ChIP-only and low grade (a grade-C TFEB model reduces to gTCACATG), so they encode promoter context as much as intrinsic specificity. Prefer HT-SELEX or methyl-HT-SELEX-supported models when the question is direct binding.",
 "references": [
  {
   "cite": "Hodgkinson CA, Moore KJ, Nakayama A, et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 1993;74:395-404.",
   "pmid": "8343963",
   "url": "https://pubmed.ncbi.nlm.nih.gov/8343963/"
  },
  {
   "cite": "Hemesath TJ, Steingrímsson E, McGill G, et al. microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev 1994;8:2770-80.",
   "pmid": "7958932",
   "url": "https://pubmed.ncbi.nlm.nih.gov/7958932/"
  },
  {
   "cite": "Lowings P, Yavuzer U, Goding CR. Positive and negative elements regulate a melanocyte-specific promoter. Mol Cell Biol 1992;12:3653-62.",
   "pmid": "1321344",
   "url": "https://pubmed.ncbi.nlm.nih.gov/1321344/"
  },
  {
   "cite": "Aksan I, Goding CR. Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo. Mol Cell Biol 1998;18:6930-8.",
   "pmid": "9819381",
   "url": "https://pubmed.ncbi.nlm.nih.gov/9819381/"
  },
  {
   "cite": "Pogenberg V, Ogmundsdóttir MH, Bergsteinsdóttir K, et al. Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF. Genes Dev 2012;26:2647-58.",
   "pmid": "23207919",
   "url": "https://pubmed.ncbi.nlm.nih.gov/23207919/"
  },
  {
   "cite": "Sardiello M, Palmieri M, di Ronza A, et al. A gene network regulating lysosomal biogenesis and function. Science 2009;325:473-7.",
   "pmid": "19556463",
   "url": "https://pubmed.ncbi.nlm.nih.gov/19556463/"
  },
  {
   "cite": "Palmieri M, Impey S, Kang H, et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 2011;20:3852-66.",
   "pmid": "21752829",
   "url": "https://pubmed.ncbi.nlm.nih.gov/21752829/"
  },
  {
   "cite": "Settembre C, Di Malta C, Polito VA, et al. TFEB links autophagy to lysosomal biogenesis. Science 2011;332:1429-33.",
   "pmid": "21617040",
   "url": "https://pubmed.ncbi.nlm.nih.gov/21617040/"
  },
  {
   "cite": "Roczniak-Ferguson A, Petit CS, Froehlich F, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 2012;5:ra42.",
   "pmid": "22692423",
   "url": "https://pubmed.ncbi.nlm.nih.gov/22692423/"
  },
  {
   "cite": "Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet 1994;8:251-5.",
   "pmid": "7874167",
   "url": "https://pubmed.ncbi.nlm.nih.gov/7874167/"
  },
  {
   "cite": "Yokoyama S, Woods SL, Boyle GM, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 2011;480:99-103.",
   "pmid": "22080950",
   "url": "https://pubmed.ncbi.nlm.nih.gov/22080950/"
  },
  {
   "cite": "Kuiper RP, Schepens M, Thijssen J, et al. Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Hum Mol Genet 2003;12:1661-9.",
   "pmid": "12837690",
   "url": "https://pubmed.ncbi.nlm.nih.gov/12837690/"
  },
  {
   "cite": "Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 2011;480:94-8.",
   "pmid": "22012259",
   "url": "https://pubmed.ncbi.nlm.nih.gov/22012259/"
  }
 ],
 "timeline": [
  {
   "year": 1992,
   "finding": "Mutagenesis of the TRP-1 promoter identifies the M box, an 11-bp element conserved between the melanocyte-specific TRP-1 and tyrosinase promoters, as a positive regulatory element.",
   "methods": "Promoter mutagenesis, transfection, DNA-protein binding assays",
   "confidence": "medium",
   "pmids": [
    "1321344"
   ],
   "open": "The M-box-binding factor was not identified."
  },
  {
   "year": 1993,
   "finding": "The mouse microphthalmia locus, whose alleles affect pigmentation, eye size, bone resorption, mast cells and hearing, is shown to encode a bHLH-ZIP protein.",
   "methods": "Insertional mutagenesis, positional cloning, expression analysis",
   "confidence": "high",
   "pmids": [
    "8343963"
   ]
  },
  {
   "year": 1994,
   "finding": "MITF binds DNA as a homodimer or as a heterodimer with TFEB, TFE3 or TFEC, defining the MiT family, and activates pigmentation genes through the M box.",
   "methods": "EMSA, dimerization assays, reporter assays",
   "confidence": "medium",
   "pmids": [
    "7958932"
   ],
   "open": "Why MiT proteins do not partner other bHLH-ZIP factors."
  },
  {
   "year": 1998,
   "finding": "A T immediately 5' of a CATGTG E-box is essential for MITF binding in vitro and in vivo, while no flank requirement was seen for CACGTG; pigmentation-gene E-boxes carry the T without exception.",
   "methods": "EMSA, reporter assays, cross-species promoter comparison",
   "confidence": "medium",
   "pmids": [
    "9819381"
   ],
   "open": "Later database models show a T/A flank around CACGTG as well, which this work did not detect."
  },
  {
   "year": 2009,
   "finding": "Most lysosomal genes share a promoter-proximal GTCACGTGAC element (CLEAR) and are coordinately regulated by TFEB, which translocates to the nucleus under lysosomal storage stress.",
   "methods": "Promoter motif analysis, expression meta-analysis, TFEB overexpression",
   "confidence": "medium",
   "pmids": [
    "19556463"
   ]
  },
  {
   "year": 2011,
   "finding": "A germline MITF E318K substitution that impairs SUMOylation is associated with melanoma and with renal cell carcinoma.",
   "methods": "Whole-genome sequencing, linkage, case-control association, functional assays",
   "confidence": "high",
   "pmids": [
    "22080950",
    "22012259"
   ]
  },
  {
   "year": 2012,
   "finding": "TFEB localization is set by phosphorylation, by ERK2 in response to nutrients and by lysosomal mTORC1 at Ser211 with 14-3-3 retention, so CLEAR occupancy is switched by nuclear entry rather than by site availability.",
   "methods": "Phosphosite mapping and mutagenesis, kinase inhibition, localization imaging",
   "confidence": "high",
   "pmids": [
    "21617040",
    "22692423"
   ]
  },
  {
   "year": 2012,
   "finding": "MITF crystal structures show a three-residue shift in the leucine zipper that kinks one helix and restricts heterodimerization, and an Ile212 nonpolar contact that explains M-box binding.",
   "methods": "X-ray crystallography, mutagenesis, mouse and human mutant analysis",
   "confidence": "high",
   "pmids": [
    "23207919"
   ]
  }
 ],
 "openQuestions": [
  "Whether the T and A flanks that every MiT/TFE model carries around CACGTG are a real binding preference or a property of the sequences the models were built from is untested: gel-shift and in vivo assays found the 5' T essential at CATGTG but no flanking requirement at CACGTG.",
  "Whether the M-box is more MiT/TFE-selective than the CLEAR box is not settled: the MITF structure attributes M-box binding to an Ile212 contact that related factors lack and reports that several of them bind the M-box weakly, but the JASPAR USF1 model also reads a T-flanked CATGTG (GTCATGTGAC).",
  "Whether MITF isoforms differ in DNA recognition is unclear: an alternatively spliced exon outside the bHLH-ZIP modulated DNA binding in vitro, but none of the database models resolves isoforms."
 ],
 "members": [
  {
   "id": "TFEC.H14CORE.1.SM.B",
   "source": "HOCOMOCO",
   "consensus": "gGTCACGTGAt",
   "bits": 17.9,
   "prov": {
    "evidence": "SM",
    "grade": "B"
   }
  },
  {
   "id": "TFEC.H14CORE.0.M.B",
   "source": "HOCOMOCO",
   "consensus": "GTCACGTGAt",
   "bits": 16.7,
   "prov": {
    "evidence": "M",
    "grade": "B"
   }
  },
  {
   "id": "TFE3.H14CORE.0.PSM.A",
   "source": "HOCOMOCO",
   "consensus": "gGTCACGTGAt",
   "bits": 15.8,
   "prov": {
    "evidence": "PSM",
    "grade": "A"
   }
  },
  {
   "id": "TFE3 (MA0831.3)",
   "source": "JASPAR",
   "consensus": "GTCACGTGAC",
   "bits": 15.4
  },
  {
   "id": "TFEB.H14CORE.0.SM.B",
   "source": "HOCOMOCO",
   "consensus": "GTCACGTGAt",
   "bits": 15,
   "prov": {
    "evidence": "SM",
    "grade": "B"
   }
  },
  {
   "id": "M04078_2.00",
   "source": "CIS-BP",
   "consensus": "CACGTGAC",
   "bits": 14.5,
   "prov": {
    "inferred": false
   }
  },
  {
   "id": "M08058_2.00",
   "source": "CIS-BP",
   "consensus": "GTCACGTGAC",
   "bits": 14.5,
   "prov": {
    "inferred": false
   }
  },
  {
   "id": "TFEC (MA0871.3)",
   "source": "JASPAR",
   "consensus": "CACGTGAC",
   "bits": 14.3
  },
  {
   "id": "M02727_2.00",
   "source": "CIS-BP",
   "consensus": "gTCACGTGAc",
   "bits": 13.5,
   "prov": {
    "inferred": false
   }
  },
  {
   "id": "MITF (MA0620.4)",
   "source": "JASPAR",
   "consensus": "gTCACGTGAc",
   "bits": 12.7
  },
  {
   "id": "MITF.H14CORE.0.P.B",
   "source": "HOCOMOCO",
   "consensus": "CaCGTGAC",
   "bits": 11.2,
   "prov": {
    "evidence": "P",
    "grade": "B"
   }
  },
  {
   "id": "TFEB (MA0692.2)",
   "source": "JASPAR",
   "consensus": "CACGTGAC",
   "bits": 10.8
  },
  {
   "id": "TFEB.H14CORE.1.P.C",
   "source": "HOCOMOCO",
   "consensus": "gTCACATG",
   "bits": 10.7,
   "prov": {
    "evidence": "P",
    "grade": "C"
   }
  },
  {
   "id": "M02773_2.00",
   "source": "CIS-BP",
   "consensus": "CACGTGA",
   "bits": 9.4,
   "prov": {
    "inferred": false
   }
  }
 ],
 "url": "https://motif.zhoulab.io/families/mitf_tfe/",
 "generated": "2026-10-21",
 "provenance": "Entry text drafted by a language model reading the primary literature; every cited PMID verified against PubMed. Computed fields derive from JASPAR 2024, HOCOMOCO v14, CIS-BP and the Vierstra archetypes. See https://motif.zhoulab.io/families/methods/"
}