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MTMR4, a phosphoinositide-specific 3'-phosphatase, regulates TFEB activity and the endocytic and autophagic pathways

Hoa Q Pham1, Kazuaki Yoshioka1, Hiromi Mohri1

  • 1Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|July 3, 2018
PubMed

Insights

Myotubularin-related protein-4 (MTMR4) is crucial for regulating endosomes and autophagosomes. Its absence impairs organelle traffic, fusion, and lysosomal pathways, impacting cellular stress responses.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphatidylinositol 3-phosphate (PI(3)P) regulates endosomal and autophagosomal traffic.
  • The specific phosphatase converting PI(3)P back to phosphatidylinositol in these compartments remains unclear.
  • Myotubularin-related proteins (MTMRs) are involved in phosphoinositide metabolism.

Purpose of the Study:

  • To investigate the subcellular localization and function of myotubularin-related protein-4 (MTMR4).
  • To elucidate MTMR4's role in the endocytic and autophagic pathways.
  • To understand MTMR4's impact on cellular response to starvation.

Main Methods:

  • Subcellular localization studies of MTMR4 in A549 cells.
  • MTMR4 knockdown experiments using RNA interference.
  • Analysis of endosome and autophagosome dynamics, including motility, fusion, and fission.
  • Assessment of lysosomal pathways and transcription factor EB (TFEB) nuclear translocation.

Main Results:

  • MTMR4 localizes to late endosomes and autophagosomes.
  • MTMR4 knockdown disrupts PI(3)P-enriched organelle dynamics, leading to enlarged endosomes and reduced autophagosomes/lysosomes.
  • Starvation-induced autophagy and lysosomal gene expression are impaired upon MTMR4 knockdown.
  • Nuclear translocation of TFEB is inhibited in MTMR4-deficient starved cells.

Conclusions:

  • MTMR4 is essential for maintaining the integrity of endocytic and autophagic pathways.
  • MTMR4 plays a critical role in organelle trafficking and fusion within the endolysosomal system.
  • MTMR4 is involved in the cellular response to nutrient starvation via TFEB regulation.
Keywords:
MTMR4TFEBautophagosomeautophagyendosomelysosomemembrane trafficphosphatidylinositol 3-phosphate

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