TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis

Narumi Suzuki, Yoshikazu Johmura, Teh Wei Wang, Toshiro Migita, Wenwen Wu, Rei Noguchi, Kiyoshi Yamaguchi, Yoichi Furukawa, Shuhei Nakamura, Ichiro Miyoshi, Tamotsu Yoshimori, Tomohiko Ohta, Makoto Nakanishi

Research output: Contribution to journalArticlepeer-review

Abstract

Preconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, fbxo22−/− mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy. Abbreviations: BBC3/PUMA: BCL2 binding component 3; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; ChIP-seq: chromatin immunoprecipitation followed by sequencing; DDB2: damage specific DNA binding protein 2; DRAM: DNA damage regulated autophagy modulator; ESR/ER: estrogen receptor 1; FMD: fasting mimicking diet; HCQ: hydroxychloroquine; KDM4B: lysine-specific demethylase 4B; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; NCOR1: nuclear receptor corepressor 1; SCF: SKP1-CUL-F-box protein; SQSTM1: sequestosome 1; TFEB: transcription factor EB.

Original languageEnglish
JournalAutophagy
DOIs
Publication statusAccepted/In press - 2021
Externally publishedYes

Keywords

  • AKT1
  • FBXO22
  • KDM4B
  • MYC
  • TP53
  • autophagy
  • hormesis
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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