1. Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.
- Author
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Talaia, Gabriel, Bentley-DeSousa, Amanda, and Ferguson, Shawn M
- Subjects
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AMYOTROPHIC lateral sclerosis , *LYSOSOMES , *CELL metabolism , *FRONTOTEMPORAL dementia , *AMINO acids , *CELL physiology - Abstract
Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD. Synopsis: In addition to their degradative functions, lysosomes play an important role in coordinating cellular responses to changes in nutrient availability. This study reveals that TBK1 is recruited to lysosomes when amino acids are abundant where it phosphorylates Rab7 and thus relieves Rab7-dependent suppression of mTORC1 signaling from lysosomes. TBK1 is recruited to lysosomes when amino acids are abundant. Rab7 (serine 72) is a substrate of TBK1 at lysosomes. Rab7 suppresses mTORC1 activity and this is relieved by TBK1-dependent phosphorylation of Rab7 on serine 72. The ALS-FTD associated E696K TBK1 mutant accumulates at lysosomes resulting in increased Rab7 phosphorylation and mTORC1 activity. TBK1 promotes mTORC1 activation by amino acids at the lysosome surface. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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