Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation.

Chunyan Li,Yan Liu,Kaixin Qiu,Xuezhi Li,Yili Wu,Qingxia Kong,Fengjuan Jiao,Yidan Liu,Xin Wang

doi:10.3389/fcell.2019.00170

Abstract

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 h 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.

Highlights

Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP), the two major pathways for protein degradation, are crucial for proteostasis (Kaganovich et al, 2008)
We reported that the half-life of Transcription Factor EB (TFEB) is around 13.5 h in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells
Proteasome inhibitioninduced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including light chain-3 (LC3), LC3-II, cathepsin D, and lysosomal-associated membrane protein 1 (LAMP1)

Summary

Introduction

Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP), the two major pathways for protein degradation, are crucial for proteostasis (Kaganovich et al, 2008) They play a critical role in the maintenance of physiological functions, e.g., cell cycle, apoptosis, stress response, etc. The 19S complexes deubiquinate and unfold the target proteins, allowing the proteins entering into the 20S proteasome, where they are rapidly degraded by various proteases (Hough et al, 1987; Arrigo et al, 1988; Dong et al, 2019). Reduced proteasome activity exacerbates the accumulation of damaged or misfolded proteins, e.g., tau and α-synuclein, which might further contribute to the pathogenesis of neurodegenerative diseases (David et al, 2002; Poppek et al, 2006; Alvarez-Castelao et al, 2014)

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