TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress
Authors: Yao Li
Huazi Xu
Wen Han
Hongyu Zhang
Mi Liu
Jing Zhang
Zhilong Zheng
Jian Xiao
Yuqin Mao
Huanwen Chen
Wanying Zhang
Kailiang Zhou
Ling Xie
Journal: Theranostics (2020)
Discipline: CLINICAL MEDICINE
Keywords: AMPK signaling pathways; Autophagy; ER stress-induced apoptosis; Spinal cord injury; TFE3.
Affiliations: Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China., Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China., University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Abstract:  Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI. 

Retracted: No

PubPeer comments:
 ![file] Acoording to your paper, the correct label should be  nuclear Addtionally, GAPDH is rich not only in cytoplasmic but also in nuclear. Please see the following information. 1. https: www.genecards.org cgi-bin carddisp.pl?gene=GAPDH keywords=GAPDH#localization 2. https: www.proteinatlas.org ENSG00000111640-GAPDH subcellular But your results showed that GAPDH CAN not be found in nuclear? would you explain? , 
 #1 Dear Clusiodes johnsoni, I appreciate your interest in our work, and thank you very much for pointing these out. For the first question, the label of u201cCytoplasmicu201dshould be u201cnuclearu201d in this Figure. This was due to an oversight at the typesetting stage. We will contact the journal and discuss about the necessity for a correction. And we are sure that this correction will not affect the results and conclusions of this article. For the second question, as you metioned that GAPDH is rich not only in cytoplasmic but also in nuclear, but GAPDH is mainly expressed in Cytoplasmic. Currently, most of the primary antibodies against GAPDH on the market are not sensitive enough, so the expression of GAPDH is difficult to be displayed via western blotting as that in this figure. After checking many high-quality articles[1-4], we also found the same blank signal of GAPDH in nuclear extracted protein via western blotting. To solve this problem in the further, we will try to use the primary antibodis you recommend. Yours sincerely, Corresponding authors References [1]tWang H, Wang N, Xu D, Ma Q, Chen Y, Xu S, Xia Q, Zhang Y, Prehn JHM, Wang G, Ying Z. Oxidation of multiple MiT TFE transcription factors links oxidative stress to transcriptional control of autophagy and lysosome biogenesis. Autophagy. 2020 Sep;16(9):1683-1696. [2]tRusmini P, Cortese K, Crippa V, Cristofani R, Cicardi ME, Ferrari V, Vezzoli G, Tedesco B, Meroni M, Messi E, Piccolella M, Galbiati M, Garru00e8 M, Morelli E, Vaccari T, Poletti A. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019 Apr;15(4):631-651. [3]tXia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. [4]tChen G, Xie W, Nah J, Sauvat A, Liu P, Pietrocola F, Sica V, Carmona-Gutierrez D, Zimmermann A, Pendl T, Tadic J, Bergmann M, Hofer SJ, Domuz L, Lachkar S, Markaki M, Tavernarakis N, Sadoshima J, Madeo F, Kepp O, Kroemer G. 3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB. EMBO Mol Med. 2019 Nov 7;11(11):e10469. ,