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Front. Cell Dev. Biol. | doi: 10.3389/fcell.2019.00170

Proteasome inhibition activates TFEB-associated autophagy-lysosome pathway

 Chunyan Li1,  Xin Wang2, Xuezhi Li2,  Kaixin Qiu1,  Fengjun Jiao2, Yidan Liu1, Qingxia Kong3 and  Yili Wu2*
  • 1Shandong University, China
  • 2Jining Medical University, China
  • 3Affiliated Hospital of Jining Medical University, China

Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP) are the two major protein degradation pathways, which are critical for proteostasis. Growing evidence indicates that proteasome inhibition-induced ALP activation is an adaptive response. Transcription Factor EB (TFEB) is a master regulator of ALP. However, the characteristics of TFEB and its role in proteasome inhibition-induced ALP activation are not fully investigated. Here we reported that the half-life of TFEB is around 13.5 hours in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells. Moreover, proteasome impairment not only promotes TFEB accumulation but also facilitates its dephosphorylation and nuclear translocation. In addition, proteasome inhibition-induced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including microtubule-associated protein 1B light chain-3 (LC3), particularly LC3-II, cathepsin D and lysosomal-associated membrane protein 1 (LAMP1). Furthermore, we demonstrated that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux. Our study advances the understanding of features of TFEB and indicates that TFEB might be a key mediator of proteasome impairment-induced ALP activation.

Keywords: Ubiquitin-Proteasome Pathway, Autophagy-lysosome pathway, TFEB, TFEB nuclear translocation, TFEB dephosphorylation

Received: 17 May 2019; Accepted: 07 Aug 2019.

Edited by:

Cesare Indiveri, University of Calabria, Italy

Reviewed by:

Firas H. Kobeissy, University of Florida, United States
Maurizio Renna, University of Cambridge, United Kingdom
Alessandro Magini, University of Perugia, Italy  

Copyright: © 2019 Li, Wang, Li, Qiu, Jiao, Liu, Kong and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Yili Wu, Jining Medical University, Jining, Shandong, China, yili_wu2004@yahoo.ca