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Updated: Jul 4, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

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The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs

Shu Yang1, Chun-Yuan Ting1, Mary A Lilly1

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular Cell
|February 7, 2024
PubMed

Insights

The GATOR2 complex protects key proteins (MiT/TFEs) from degradation, maintaining lysosome function. This discovery reveals GATOR2

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Lysosomes are crucial for cellular metabolic homeostasis.
  • Microphthalmia bHLH-LZ transcription factors (MiT/TFEs) regulate lysosomal and autophagic genes.
  • MiT/TFEs are frequently dysregulated in various cancers.

Purpose of the Study:

  • To investigate the role of the GATOR2 complex in maintaining lysosomal function.
  • To determine the mechanism by which GATOR2 influences MiT/TFEs.
  • To explore GATOR2's relevance in MiT/TFE-driven cancers.

Main Methods:

  • Utilized GATOR2 knockout HeLa cells to study MiT/TFE degradation.
  • Investigated ubiquitylation of MiT/TFEs by E3 ligases.
  • Analyzed GATOR2's protective role in cancer cell lines (pancreatic ductal adenocarcinoma, Xp11 translocation renal cell carcinoma).

Main Results:

  • GATOR2 protects MiT/TFEs from proteasomal degradation independently of TORC1.
  • Loss of GATOR2 leads to MiT/TFE ubiquitylation and degradation, causing lysosome dysfunction.
  • GATOR2 protects MiT/TFE proteins in cancers driven by MiT/TFE hyperactivation.

Conclusions:

  • GATOR2 complex plays an independent role in regulating TORC1.
  • GATOR2 is essential for protecting MiT/TFE proteins from degradation.
  • GATOR2 is central to coordinating cellular metabolism and the lysosomal-autophagic system.
Keywords:
E3 ligasesGATOR2MiT/TFEsTORC1autophagylysosomepancreatic ductal adenocarcinomarenal cell carcinomaubiquitination

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