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Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules
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Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage

Jingyue Jia1,2, Fulong Wang1,2, Zambarlal Bhujabal3

  • 1University of New Mexico Health Sicences Center, Albuquerque, New Mexico, USA.

Autophagy
|November 17, 2022
PubMed

Insights

Lysosomal damage triggers stress granules (SGs) that inhibit protein synthesis via eIF2α phosphorylation. Mammalian Atg8 proteins (mATG8s) coordinate SG formation and MTOR inactivation, controlling cellular responses to lysosomal damage.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Mammalian Atg8 proteins (mATG8s) have functions beyond canonical autophagy, including Atg8ylation.
  • Mechanistic target of rapamycin (MTOR) and stress granules (SGs) regulate global protein synthesis under stress.
  • Lysosomal damage is a cellular stressor that can impact protein synthesis and cellular homeostasis.

Purpose of the Study:

  • To investigate the role of lysosomal damage in inducing stress granules (SGs).
  • To elucidate the involvement of mATG8 proteins in the cellular response to lysosomal damage.
  • To understand how SGs and mATG8s coordinate protein synthesis inhibition and MTOR signaling.

Main Methods:

  • Induction of stress granules using lysosome-damaging agents and viral proteins (SARS-CoV-2 ORF3a).
  • Proteomic analysis to identify proteins recruited to damaged lysosomes.
  • Investigating protein-protein interactions and the role of Atg8ylation in protein recruitment and function.

Main Results:

  • Lysosomal damage induces SGs, which inhibit protein translation through eukaryotic translation initiation factor 2A (eIF2α) phosphorylation and activate the integrated stress response.
  • Core SG proteins (NUFIP2, G3BP1) and GABARAP family members of mATG8s are recruited to damaged lysosomes independently of SG condensates or canonical autophagy.
  • GABARAPs interact with NUFIP2 and G3BP1, and Atg8ylation is crucial for their lysosomal recruitment; NUFIP2 mediates MTOR inactivation at the lysosome.

Conclusions:

  • Cells utilize membrane Atg8ylation to regulate SG formation and MTOR inactivation in response to lysosomal damage.
  • The study reveals a novel mechanism where lysosomal damage triggers SGs that inhibit translation, coordinated by mATG8s.
  • Separable functions of NUFIP2 and G3BP1 in SG assembly and MTOR inactivation are modulated by GABARAP and Atg8ylation.
Keywords:
Atg8ylationMTORMycobacterium tuberculosisNUFIP2PKRSARS-CoV-2 ORF3aintegrated stress responselysosomal damageproteopathic taustress granules

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