Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI:10.1038/s44318-024-00180-8
Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson
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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.

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溶酶体 TBK1 对氨基酸的可用性做出反应,以缓解 Rab7 依赖性 mTORC1 的抑制作用。
溶酶体在协调大分子降解以及调节细胞生长和新陈代谢方面发挥着关键作用。尽管在鉴定溶酶体信号蛋白方面取得了重大进展,但对使溶酶体功能与不断变化的细胞需求同步的途径的了解仍然不全面。本研究发现了 TANK 结合激酶 1(TBK1)在调节溶酶体对营养物质的反应能力方面的作用,TBK1 因其在先天性免疫和细胞器质量控制中的作用而广为人知。具体来说,我们发现了一个 TBK1 池,它在氨基酸水平升高时被招募到溶酶体。这种溶酶体 TBK1 会使 Rab7 的丝氨酸 72 磷酸化。这对于减轻 Rab7 介导的氨基酸依赖性 mTORC1 激活的抑制作用至关重要。此外,一种与肌萎缩性侧索硬化症和额颞叶痴呆症相关的 TBK1 突变体(E696K)会在溶酶体中蓄积,导致 Rab7 磷酸化升高和 mTORC1 激活增加。这一数据证实溶酶体是氨基酸调控 TBK1 信号的场所,对有效激活 mTORC1 至关重要。这种溶酶体 TBK1 池对溶酶体的稳态具有更广泛的意义,它的失调可能导致 ALS-FTD 的发病机制。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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