TFE3, also known as transcription factor binding to IGHM enhancer 3, is a member of the MiT family of the bHLH-leucine zipper transcription factor. It plays a crucial role in multiple biological processes. TFE3 participates in energy metabolism, regulating pathways such as glucose and lipid metabolism, mitochondrial metabolism, and autophagy [6]. It also serves as a master transcriptional regulator of autophagy and lysosomal activity [2].

In disease-related research, TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare kidney cancer subtype. ASPSCR1-TFE3 fusion and some somatic copy number alterations are linked to aggressive features and poor outcomes in TFE3-tRCC [1]. TFE3-immunopositive papillary renal cell carcinoma without TFE3 gene rearrangement shows a poorer prognosis and is correlated with expressions of autophagy/lysosome proteins [3]. TFE3-rearranged perivascular epithelioid cell tumors (PEComas) often show aggressive behavior, and the use of mTOR inhibitors seems ineffective [4]. In spinal cord injury, TFE3 may be a potential therapeutic target as it can augment autophagy flux and alleviate ER stress [5]. Conditional, beta-cell-specific Tfeb/Tfe3 double-KO mice showed severe alteration of insulin transcription, secretion, and glucose tolerance, indicating TFE3's role in glucose homeostasis [7]. In Birt-Hogg-Dubé syndrome, both TFEB and TFE3 contribute to kidney cystogenesis and tumorigenesis, as shown by Flcn/Tfeb/Tfe3 triple KO mice [8].

In summary, TFE3 is essential in metabolic regulation, autophagy, and lysosomal activity. Model-based research, especially KO/CKO mouse models, has revealed its significance in various disease conditions such as kidney cancers, spinal cord injury, glucose homeostasis-related disorders, and Birt-Hogg-Dubé syndrome-associated cystogenesis and tumorigenesis.

References:

1. Sun, Guangxi, Chen, Junru, Liang, Jiayu, Chen, Ni, Zeng, Hao. 2021. Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma. In Nature communications, 12, 5262. doi:10.1038/s41467-021-25618-z. https://pubmed.ncbi.nlm.nih.gov/34489456/

2. Paquette, Mathieu, El-Houjeiri, Leeanna, C Zirden, Linda, Siegel, Peter M, Pause, Arnim. 2021. AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3. In Autophagy, 17, 3957-3975. doi:10.1080/15548627.2021.1898748. https://pubmed.ncbi.nlm.nih.gov/33734022/

3. Takamatsu, Dai, Kohashi, Kenichi, Kiyozawa, Daisuke, Eto, Masatoshi, Oda, Yoshinao. 2023. TFE3-immunopositive papillary renal cell carcinoma: A clinicopathological, immunohistochemical, and genetic study. In Pathology, research and practice, 242, 154313. doi:10.1016/j.prp.2023.154313. https://pubmed.ncbi.nlm.nih.gov/36669395/

4. Argani, Pedram, Gross, John M, Baraban, Ezra, Suurmeijer, Albert J H, Antonescu, Cristina R. 2024. TFE3 -Rearranged PEComa/PEComa-like Neoplasms : Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy. In The American journal of surgical pathology, 48, 777-789. doi:10.1097/PAS.0000000000002218. https://pubmed.ncbi.nlm.nih.gov/38597260/

5. Zhou, Kailiang, Zheng, Zhilong, Li, Yao, Xu, Huazi, Xiao, Jian. 2020. TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress. In Theranostics, 10, 9280-9302. doi:10.7150/thno.46566. https://pubmed.ncbi.nlm.nih.gov/32802192/

6. Li, Xingyu, Chen, Yongming, Gong, Siqiao, Li, Xiaoyu, Hao, Junfeng. 2023. Emerging roles of TFE3 in metabolic regulation. In Cell death discovery, 9, 93. doi:10.1038/s41420-023-01395-0. https://pubmed.ncbi.nlm.nih.gov/36906611/

7. Pasquier, Adrien, Pastore, Nunzia, D'Orsi, Luca, Napolitano, Gennaro, Ballabio, Andrea. 2023. TFEB and TFE3 control glucose homeostasis by regulating insulin gene expression. In The EMBO journal, 42, e113928. doi:10.15252/embj.2023113928. https://pubmed.ncbi.nlm.nih.gov/37712288/

8. Di Malta, Chiara, Zampelli, Angela, Granieri, Letizia, Linehan, W Marston, Ballabio, Andrea. 2023. TFEB and TFE3 drive kidney cystogenesis and tumorigenesis. In EMBO molecular medicine, 15, e16877. doi:10.15252/emmm.202216877. https://pubmed.ncbi.nlm.nih.gov/36987696/