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

Jia, Jingyue; Wang, Fulong; Bhujabal, Zambarlal; Peters, Ryan; Mudd, Michal; Duque, Thabata; Allers, Lee; Javed, Ruheena; Salemi, Michelle; Behrends, Christian; Phinney, Brett; Johansen, Terje and Deretic, Vojo (2022): Stress granules and mTOR are regulated by membrane atg8ylation during lysosomal damage. In: Journal of Cell Biology, Vol. 221, No. 11, e202207091

Abstract

Lysosomal damage induces stress granule (SG) formation and translational reprograming. The newly appreciated process of atg8ylation affects SG formation and concomitantly recruits SG core proteins NUFIP2 and G3BP1 to damaged lysosomes. These proteins independently of SG condensates and in coordination with galectin-8 inactivate mTOR via the Ragulator-Rag complex. We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2(ORF3a), Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator-RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Munich Cluster for Systems Neurology (SyNergy)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0021-9525
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198