open access publication

Article, 2024

Targeted dephosphorylation of TFEB promotes its nuclear translocation

iScience, ISSN 2589-0042, Volume 27, 8, Page 110432, 10.1016/j.isci.2024.110432

Contributors

Zhao, Jin-Feng [1] Shpiro, Natalia [1] Sathe, Gajanan J 0000-0002-6239-5365 [1] Brewer, Abigail [1] Macartney, Thomas J 0000-0002-6745-183X [1] Wood, Nicola T 0000-0002-3347-6625 [1] Negoita, Florentina 0000-0001-6032-0127 [2] Sakamoto, Kei (Corresponding author) [2] Sapkota, Gopal P (Corresponding author) [1]

Affiliations

  1. [1] University of Dundee
    2. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  2. [2] University of Copenhagen
    3. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD]

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.

Keywords

TFEB phosphorylation, absence, activating transcription factor EB, activation of transcription factor EB, activity, cells, cellular responses, cellular stress, conditions, coordinated cellular response, cytoplasm, dephosphorylation, dephosphorylation of transcription factor EB, deprivation, endogenous levels, induced nuclear translocation, induction, levels, nuclear translocation, nutrient deprivation, phosphatase, phosphorylates TFEB, phosphorylation, proximity, response, reversible phosphorylation, stress, study, system, targeted dephosphorylation, transcription, transcription factor EB, transcriptional activity, translocation

Funders

  • GlaxoSmithKline (United Kingdom)
  • Biotechnology and Biological Sciences Research Council
  • Merck (Germany)
  • Medical Research Council
  • Novo Nordisk Foundation
  • Novo Nordisk (Denmark)

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