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Programmed cell death 4 modulates lysosomal function by inhibiting TFEB translation.

Xiaotong Chen1, Yetong Guan1, Yi Zhang1

  • 1Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.

Cell Death and Differentiation
|October 26, 2020
PubMed
Summary
This summary is machine-generated.

Programmed cell death 4 (PDCD4) suppresses TFEB translation, inhibiting lysosome biogenesis. This PDCD4-TFEB interaction offers a new therapeutic target for lysosome dysfunction diseases.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transcription factor EB (TFEB) regulates autophagy and lysosomal biogenesis.
  • TFEB activity is modulated by post-translational phosphorylation via mTOR and ERK signaling.
  • Translational regulation of TFEB remains largely unexplored.

Purpose of the Study:

  • To investigate the role of programmed cell death 4 (PDCD4) in regulating TFEB.
  • To elucidate the mechanism by which PDCD4 affects TFEB levels and function.
  • To explore the therapeutic potential of targeting the PDCD4-TFEB axis in diseases.

Main Methods:

  • Western blotting to assess protein levels.
  • Immunofluorescence microscopy for subcellular localization.
  • RNA immunoprecipitation assays to study translation.
  • In vitro assays to confirm protein-protein interactions.

Main Results:

  • PDCD4 significantly reduces nuclear TFEB levels, inhibiting lysosome biogenesis and function.
  • PDCD4 suppresses TFEB translation via an eIF4A-dependent mechanism, independent of mTOR and ERK signaling.
  • Both MA3 domains of PDCD4 are essential for inhibiting TFEB translation.
  • PDCD4 deficiency enhances TFEB expression in the tumor microenvironment, promoting anti-tumor macrophage activity.

Conclusions:

  • PDCD4 acts as a novel translational repressor of TFEB.
  • PDCD4-mediated translational control of TFEB impacts lysosomal function.
  • Targeting PDCD4 may offer a therapeutic strategy for lysosome-related disorders and cancer.