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

Jee-Yun Park1, Sunhyo Kim1, Hee Young Sohn1

  • 1Division of Brain Diseases, Center for Biomedical Science, Korea National Institute of Health, 187 Osongsaengmyeong 2-ro, Osong-eup, Cheongju-si, Chungcheongbuk-do, 28159, Korea.

Scientific Reports
|October 6, 2019
PubMed

Insights

Transcriptional factor EB (TFEB) activates nuclear factor E2-related factor 2 (Nrf2) by increasing its stability. This study reveals TFEB enhances Nrf2-response genes independent of oxidative stress.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Transcriptional factor EB (TFEB) and nuclear factor E2-related factor 2 (Nrf2) are key regulators of cellular stress responses.
  • The interplay between TFEB and Nrf2 has not been previously elucidated.

Purpose of the Study:

  • To investigate the relationship between TFEB and Nrf2.
  • To determine if TFEB influences Nrf2 activity and stability.

Main Methods:

  • Generation of human neuroglioma cell lines with stable TFEB expression.
  • Analysis of Nrf2-response gene expression (HO-1, GSTM1, p62).
  • Assessment of Nrf2 protein levels, ubiquitination, and interaction with regulatory proteins (DCAF11, Keap1).

Main Results:

  • TFEB overexpression induced Nrf2-response genes independently of oxidative stress.
  • Nrf2 protein levels increased, and its ubiquitination decreased in TFEB-expressing cells.
  • TFEB downregulated DCAF11 and increased p62 phosphorylation, leading to Nrf2 stabilization.

Conclusions:

  • TFEB activates Nrf2 by enhancing its protein stability, not through oxidative stress pathways.
  • TFEB-mediated repression of DCAF11 and modulation of p62 contribute to Nrf2 stabilization.
  • This study establishes a novel mechanism of Nrf2 regulation by TFEB.

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