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

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...
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Autor*in:	Talaia, Gabriel [verfasserIn] Bentley-DeSousa, Amanda [verfasserIn] Ferguson, Shawn M [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Lysosome Nutrient Sensing mTORC1 ALS-FTD TBK1

Anmerkung:	© The Author(s) 2024

Übergeordnetes Werk:	Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 43(2024), 18 vom: 05. Aug., Seite 3948-3967
Übergeordnetes Werk:	volume:43 ; year:2024 ; number:18 ; day:05 ; month:08 ; pages:3948-3967

Links:	Volltext

DOI / URN:	10.1038/s44318-024-00180-8

Katalog-ID:	SPR057347239

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520			\|a 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.
520			\|a 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.
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allfields	10.1038/s44318-024-00180-8 doi (DE-627)SPR057347239 (SPR)s44318-024-00180-8-e DE-627 ger DE-627 rakwb eng Talaia, Gabriel verfasserin (orcid)0000-0003-1870-4658 aut Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213 Bentley-DeSousa, Amanda verfasserin aut Ferguson, Shawn M verfasserin (orcid)0000-0002-3092-7718 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 18 vom: 05. Aug., Seite 3948-3967 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967 https://dx.doi.org/10.1038/s44318-024-00180-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2050 GBV_ILN_2059 GBV_ILN_2118 GBV_ILN_2153 GBV_ILN_2472 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 18 05 08 3948-3967
spelling	10.1038/s44318-024-00180-8 doi (DE-627)SPR057347239 (SPR)s44318-024-00180-8-e DE-627 ger DE-627 rakwb eng Talaia, Gabriel verfasserin (orcid)0000-0003-1870-4658 aut Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213 Bentley-DeSousa, Amanda verfasserin aut Ferguson, Shawn M verfasserin (orcid)0000-0002-3092-7718 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 18 vom: 05. Aug., Seite 3948-3967 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967 https://dx.doi.org/10.1038/s44318-024-00180-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2050 GBV_ILN_2059 GBV_ILN_2118 GBV_ILN_2153 GBV_ILN_2472 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 18 05 08 3948-3967
allfields_unstemmed	10.1038/s44318-024-00180-8 doi (DE-627)SPR057347239 (SPR)s44318-024-00180-8-e DE-627 ger DE-627 rakwb eng Talaia, Gabriel verfasserin (orcid)0000-0003-1870-4658 aut Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213 Bentley-DeSousa, Amanda verfasserin aut Ferguson, Shawn M verfasserin (orcid)0000-0002-3092-7718 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 18 vom: 05. Aug., Seite 3948-3967 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967 https://dx.doi.org/10.1038/s44318-024-00180-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2050 GBV_ILN_2059 GBV_ILN_2118 GBV_ILN_2153 GBV_ILN_2472 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 18 05 08 3948-3967
allfieldsGer	10.1038/s44318-024-00180-8 doi (DE-627)SPR057347239 (SPR)s44318-024-00180-8-e DE-627 ger DE-627 rakwb eng Talaia, Gabriel verfasserin (orcid)0000-0003-1870-4658 aut Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213 Bentley-DeSousa, Amanda verfasserin aut Ferguson, Shawn M verfasserin (orcid)0000-0002-3092-7718 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 18 vom: 05. Aug., Seite 3948-3967 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967 https://dx.doi.org/10.1038/s44318-024-00180-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2050 GBV_ILN_2059 GBV_ILN_2118 GBV_ILN_2153 GBV_ILN_2472 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 18 05 08 3948-3967
allfieldsSound	10.1038/s44318-024-00180-8 doi (DE-627)SPR057347239 (SPR)s44318-024-00180-8-e DE-627 ger DE-627 rakwb eng Talaia, Gabriel verfasserin (orcid)0000-0003-1870-4658 aut Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 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. Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213 Bentley-DeSousa, Amanda verfasserin aut Ferguson, Shawn M verfasserin (orcid)0000-0002-3092-7718 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 18 vom: 05. Aug., Seite 3948-3967 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967 https://dx.doi.org/10.1038/s44318-024-00180-8 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2050 GBV_ILN_2059 GBV_ILN_2118 GBV_ILN_2153 GBV_ILN_2472 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 43 2024 18 05 08 3948-3967
language	English
source	Enthalten in The EMBO Journal 43(2024), 18 vom: 05. Aug., Seite 3948-3967 volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967
sourceStr	Enthalten in The EMBO Journal 43(2024), 18 vom: 05. Aug., Seite 3948-3967 volume:43 year:2024 number:18 day:05 month:08 pages:3948-3967
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Lysosome Nutrient Sensing mTORC1 ALS-FTD TBK1
isfreeaccess_bool	true
container_title	The EMBO Journal
authorswithroles_txt_mv	Talaia, Gabriel @@aut@@ Bentley-DeSousa, Amanda @@aut@@ Ferguson, Shawn M @@aut@@
publishDateDaySort_date	2024-08-05T00:00:00Z
hierarchy_top_id	266022529
id	SPR057347239
language_de	englisch
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author	Talaia, Gabriel
spellingShingle	Talaia, Gabriel misc Lysosome misc Nutrient Sensing misc mTORC1 misc ALS-FTD misc TBK1 Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
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topic_title	Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition Lysosome (dpeaa)DE-He213 Nutrient Sensing (dpeaa)DE-He213 mTORC1 (dpeaa)DE-He213 ALS-FTD (dpeaa)DE-He213 TBK1 (dpeaa)DE-He213
topic	misc Lysosome misc Nutrient Sensing misc mTORC1 misc ALS-FTD misc TBK1
topic_unstemmed	misc Lysosome misc Nutrient Sensing misc mTORC1 misc ALS-FTD misc TBK1
topic_browse	misc Lysosome misc Nutrient Sensing misc mTORC1 misc ALS-FTD misc TBK1
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
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title	Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
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title_full	Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
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author_browse	Talaia, Gabriel Bentley-DeSousa, Amanda Ferguson, Shawn M
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title_sort	lysosomal tbk1 responds to amino acid availability to relieve rab7-dependent mtorc1 inhibition
title_auth	Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
abstract	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. © The Author(s) 2024
abstractGer	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. © The Author(s) 2024
abstract_unstemmed	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. © The Author(s) 2024
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title_short	Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
url	https://dx.doi.org/10.1038/s44318-024-00180-8
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