Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage

Area of Science:

• Cell Biology
• Molecular Biology
• Stress Response

Background:

• Lysosomal damage is a critical cellular event with significant implications for cell fate.
• Stress granules (SGs) are cytoplasmic aggregates formed under various stress conditions.
• The interplay between lysosomal integrity and SG formation remains largely unexplored.

Purpose of the Study:

• To investigate the role of lysosomal damage as an inducer of stress granule formation.
• To elucidate the molecular mechanisms coordinating SG formation and mTOR signaling during lysosomal stress.
• To identify novel pathways involved in cellular responses to lysosomal damage.

Main Methods:

• Induction of lysosomal damage using agents like SARS-CoV-2 ORF3a, Mycobacterium tuberculosis, and proteopathic tau.
• Investigation of mammalian ATG8 protein interactions with core SG proteins (NUFIP2, G3BP1) during lysosomal stress.
• Analysis of the role of membrane atg8ylation in protein recruitment to damaged lysosomes and mTOR inactivation via the Ragulator-RagA/B complex.

Main Results:

• Lysosomal damage was identified as a novel inducer of stress granule formation.
• The process of membrane atg8ylation was found to coordinate SG formation with mTOR inactivation.
• Mammalian ATG8s directly interacted with NUFIP2 and G3BP1, facilitating their recruitment to damaged lysosomes.
• NUFIP2 was implicated in mTOR inactivation through the Ragulator-RagA/B complex.

Conclusions:

• Cells utilize membrane atg8ylation to manage and integrate stress granule and mTOR responses to lysosomal damage.
• This study reveals a new layer of cellular regulation linking lysosomal health to broader stress response pathways.
• Understanding membrane atg8ylation offers insights into cellular defense mechanisms against various pathogenic insults and proteopathies.