Targeted dephosphorylation of TFEB promotes its nuclear translocation

Jin-Feng Zhao, Natalia Shpiro, Gajanan Sathe, Abigail Brewer, Thomas J. Macartney, Nicola Wood, Florentina Negoita, Kei Sakamoto (Lead / Corresponding author), Gopal P. Sapkota (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.

Original languageEnglish
Article number110432
JournaliScience
Volume27
Issue number8
Early online date29 Jun 2024
DOIs
Publication statusE-pub ahead of print - 29 Jun 2024

Keywords

  • Health sciences
  • Medical specialty
  • Medicine
  • Precision medicine

ASJC Scopus subject areas

  • General

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