TFEB activates Nrf2 by repressing its E3 ubiquitin ligase DCAF11 and promoting phosphorylation of p62

Jee-Yun Park,Sunhyo Kim,Chulman Jo,Young Ho Koh,Hee Young Sohn

doi:10.1038/s41598-019-50877-8

Jee-Yun Park, Sunhyo Kim + Show 3 more

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https://doi.org/10.1038/s41598-019-50877-8

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Journal: Scientific Reports	Publication Date: Oct 4, 2019
Citations: 27	License type: open-access

Affiliation: Korea National Institute of Health

Abstract

Transcriptional factor EB (TFEB) and nuclear factor E2-related factor 2 (Nrf2) play crucial roles in the biological response against cellular stressors; however, their relationship has not yet been investigated. Here, we constructed human neuroglioma cell lines stably expressing TFEB. The expression of Nrf2-response genes, including heme oxygenase (HO)-1, glutathione-s-transferase-mu1 (GSTM1), and p62, was induced in the cell line, independent of oxidative stress. Of note, the protein level of Nrf2 was significantly increased, and its ubiquitinated fraction was reduced in stable cells compared to that in the control cells. Among E3 ubiquitin ligases known to be involved in the ubiquitination of Nrf2, DDB1 and Cullin4 associated factor 11 (DCAF11) was down-regulated at both protein and mRNA levels in stable cells, indicating that the repression of DCAF11 by TFEB may be mainly involved in the stabilization of Nrf2. In addition, the level of phosphorylated p62 at S349 was highly increased in stable cells compared to that in control cells, which could allow it to interfere with the association of Keap1 and Nrf2, thus stabilizing Nrf2. We suggest for the first time that TFEB could activate Nrf2 by increasing its stability under conditions devoid of oxidative stress.

Highlights

The transcriptional factor nuclear factor E2-related factor 2 (Nrf2) regulates genes involved in the cellular response against various stressors, including oxidative stress[1,2]
An increased protein level in lysosomal proteins was observed in transcriptional factor EB (TFEB) cells (Supplementary Fig. S1b), indicating that TFEB activity was highly induced in the cell line stably expressing TFEB
The results strongly suggest that TFEB could increase Nrf[2] activity

Summary

Introduction

The transcriptional factor nuclear factor E2-related factor 2 (Nrf2) regulates genes involved in the cellular response against various stressors, including oxidative stress[1,2]. Two molecules of Keap[1] bind to the ETGE and DLG motifs in the Neh[2] domain of Nrf[2] and recruit the Cul3/Rbx1complex, leading to its ubiquitination and subsequent proteasomal degradation[8,9,10]. Growing evidence suggests that Nrf[2] and TFEB would cooperate against cellular stresses and for protein homeostasis[15,26,27,28] Both transcriptional factors were known to cooperatively participate in the clearance of phosphorylated tau, which is a component of neurofibrillary tangles in the patient brains of Alzheimer’s disease[29,30]. We describe a novel molecular mechanism in which TFEB activates Nrf[2] under conditions devoid of oxidative stress

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Conclusion