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Emerging Roles and Regulation of Mit/TFE Transcriptional Factors Yang et al. Cell Communication and Signaling (2018) 16:31 https://doi.org/10.1186/s12964-018-0242-1 REVIEW Open Access Emerging roles and regulation of MiT/TFE transcriptional factors Min Yang1†, En Liu1†, Li Tang1, Yuanyuan Lei1, Xuemei Sun1, Jiaxi Hu1, Hui Dong1,2, Shi-Ming Yang1, Mingfa Gao3* and Bo Tang1* Abstract The MiT/TFE transcription factors play a pivotal role in the regulation of autophagy and lysosomal biogenesis. The subcellular localization and activity of MiT/TFE proteins are primarily regulated through phosphorylation. And the phosphorylated protein is retained in the cytoplasm and subsequently translocates to the nucleus upon dephosphorylation, where it stimulates the expression of hundreds of genes, leading to lysosomal biogenesis and autophagy induction. The transcription factor-mediated lysosome-to-nucleus signaling can be directly controlled by several signaling molecules involved in the mTORC1, PKC, and AKT pathways. MiT/TFE family members have attracted much attention owing to their intracellular clearance of pathogenic factors in numerous diseases. Recently, multiple studies have also revealed the MiT/TFE proteins as master regulators of cellular metabolic reprogramming, converging on autophagic and lysosomal function and playing a critical role in cancer, suggesting that novel therapeutic strategies could be based on the modulation of MiT/TFE family member activity. Here, we present an overview of the latest research on MiT/TFE transcriptional factors and their potential mechanisms in cancer. Keywords: TFEB, TFE3, MiT/TFE family, Lysosome, Autophagy, Cancer Background MiT/TFE family of transcription factors The Microphthalmia family of bHLH-LZ transcription The Microphthalmia family of bHLH-LZ transcription fac- factors (MiT/TFE) is composed of four members. Previ- tors (MiT/TFE) is composed of four members: MITF, ous studies reveal that the MiT/TFE transcriptional fac- TFEB, TFE3 and TFEC [1, 2]. All members of the MiTF/ tors play important roles in the regulation of cellular TFE family share a similar structure that includes three crit- processes. In particular, recent evidence suggests that ically important regions. The basic motif, which is required the MiT/TFE family members might function as critical for DNA binding, and highly similar Helix-loop-helix factors in cancer. In this review, we focus on the novel (HLH) and leucine-zipper (Zip) regions are important for mechanism involved in the regulation of the activation their dimerization; however, outside of these regions, these of MiT/TFE transcriptional factors and their role in proteins are quite different [3]. Besides, TFEB, TFE3 and lysosomal homeostasis and autophagy induction. We MITF also contain a conserved activation domain that is also describe the participation of the aberrant activation important for their transcriptional activation [1], while the of MiT/TFE members in cancer and discuss the poten- activation domain is missing in TFEC, which is the most di- tial therapeutic strategy in cancer. vergent member of the family and appears to inhibit, rather than activate, transcription [4]. Homodimerization and heterodimerization within the members of the MiTF/TFE family is critical for binding to DNA and the transcriptional activation of target * Correspondence: [email protected]; [email protected] genes [5]. MiT/TFE members bind the palindromic † Min Yang and En Liu contributed equally to this work. CACGTG E-box, a motif also recognized by other 3Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 40037, China bHLH-Zip transcription factors, such as MYC, MAX 1Department of Gastroenterology, Xinqiao Hospital, Third Military Medical and MAD proteins [6]. Unlike other bHLH-Zip tran- University (Army Medical University), Chongqing 400037, China scription factors, MiT/TFE proteins also specifically bind Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Cell Communication and Signaling (2018) 16:31 Page 2 of 11 the asymmetric TCATGTG M-box response elements Role of MiT/TFE family in lysosome and present in the promoter region of their downstream tar- autophagy biogenesis get genes [7]. However, MiT/TFE proteins do not het- Role of MiT/TFE in the transcriptional regulation of erodimerize with other bHLH-Zip-containing proteins lysosome biogenesis directly, such as MYC and USF [5, 6]. A previous study Lysosomes are crucial components of the cellular deg- demonstrated that a conserved three-residue shift within radation and recycling system, and their correct function the Zip domain of the MiT/TFE members generates an is required to maintain proper cell homeostasis [26]. unusual out-of-register leucine zipper that allows for These organelles are indeed involved in a number of specific heterodimerization among MiT/TFE members, essential cellular processes, including autophagy and while preventing binding to other bHLH-Zip transcrip- lysosomal exocytosis [27]. Autophagosome clearance is tion factors [5]. However, the functional relevance of initiated upon fusion with lysosomes and/or late endo- MiT/TFE homodimers compared to heterodimers re- somes, which introduce into the resulting autolysosome mains unknown. dozens of lysosomal acidic hydrolases and the acidifica- All four MiT/TFE members are conserved in verte- tion machinery necessary for enzyme activation and brates [8]. The MITF gene is predominantly expressed substrate digestion [28]. in the retinal pigment epithelium (RPE), macrophages, Lysosomes have long been considered as static organ- osteoclasts, mast cells, melanocytes and natural killer elles devoted to the terminal degradation of waste cells [2], while TFEC expression is restricted to cells of material; however, this concept has been challenged by myeloid origin [9]. In contrast, TFE3 and TFEB show a subsequent discoveries that lysosomal biogenesis and more ubiquitous pattern of expression and have been function are subject to transcriptional regulation [1, 29]. detected in multiple cell types [10]. A large body of The promoter analysis of lysosomal genes revealed that evidence suggests that the expression of MITF isoforms these molecules share a common 10-base E-box-like pal- (this expression is different in the amino-terminal re- indromic sequence (GTCACGTGAC), in most cases, lo- gions) is due to alternative splicing and posttranslational calized within 200 base pairs of the transcription modifications [11]. Many of these isoforms show a initiation site. This motif was named Coordinated Lyso- tissue-dependent manner due to the usage of alternative somal Expression and Regulation (CLEAR) element [30]. promoters. For example, MITF-M is mainly expressed in TFE3 and TFEB directly bind to CLEAR elements on melanoblasts and melanocytes, MITF-D is preferentially the promoters of several autophagic lysosomal genes to expressed in monocyte lineages [12], and MITF-A promote their expression [31, 32]. Accordingly, TFEB and MITF-H can be detected in several cells [3]. and TFE3 overexpression increases the number of lyso- Analyzing their molecular structures, we conclude somes and levels of lysosomal enzymes, thus promoting that TFEB and TFEC contain multiple alternative first lysosomal catabolic activity [2, 30], while the depletion exons with restricted and differential tissue distribu- of these genes abolishes the enhanced expression of tions, whereas the TFE3 gene may be regulated by a lysosomal genes [2, 33]. Moreover, previous studies have single promoter [13]. also shown that TFEB can induce lysosomal exocytosis Numerous studies have provided evidence suggesting that [34], a process by which lysosomes fuse to the plasma MiT/TFE transcription factors are important for the main- membrane and secrete their contents into the extracellu- tenance of cellular physiological and pathological processes. lar space, suggesting the transcriptional regulation of Among all the four members of the MiT/TFE family, TFEC lysosome function which promotes intracellular clear- is the least studied, and its function has not been widely in- ance by TFEB. In a recent study, the role of MITF in the vestigated [14]. While MITF is critical for proliferation, sur- regulation of lysosomal biogenesis has been established vival and differentiation of melanocytes [3, 15]. And in multiple cell types [35, 36]. MITF-A is localized at the Mutations in MITF are also linked to the pigment and deaf- lysosomal membrane, mimicking the transcriptional ness disorder, Waardenburg syndrome type 2A [9]. And the regulation of TFEB and TFE3 [37], and MITF-M drives presentation of TFE3 and TFEB is correlated with the devel- the transcription of lysosomal markers and activates the opment of osteoclasts [16], mast cell differentiation [17, 18], CLEAR motif reporter in melanoma cells [36]. regulation of the expression of genes encoding critical meta- Notably, TFEB overexpression
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