Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition

Figlia, Gianluca; Müller, Simon; Hagenston, Anna M.; Kleber, Susanne; Roiuk, Mykola; Quast, Jan-Philipp; Bosch, Nora ten; Ibañez, Damian Carvajal; Mauceri, Daniela; Martín-Villalba, Ana; Teleman, Aurelio A.

doi:10.1038/s41556-022-00977-x

Cited by 15 publications

(18 citation statements)

References 75 publications

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“…However, they may provide sites for post-translational modifications or interaction motifs for regulatory proteins, as we report here for p18 preferentially binding to RagD. Accordingly, in an accompanying paper, Figlia et al reveal that RagB isoforms maintain active mTORC1 in starved neurons or various tumours by inhibiting GATOR1, the RagA/B GTPase activating protein complex 55 .…”

Section: Discussionsupporting

confidence: 68%

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids

et al. 2022

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Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA–D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Here, by using genetically modified cell lines that express single Rag heterodimers, we uncover a Rag dimer code that determines how amino acids regulate mTORC1. First, RagC/D differentially define the substrate specificity downstream of mTORC1, with RagD promoting phosphorylation of its lysosomal substrates TFEB/TFE3, while both Rags are involved in the phosphorylation of non-lysosomal substrates such as S6K. Mechanistically, RagD recruits mTORC1 more potently to lysosomes through increased affinity to the anchoring LAMTOR complex. Furthermore, RagA/B specify the signalling response to amino acid removal, with RagB-expressing cells maintaining lysosomal and active mTORC1 even upon starvation. Overall, our findings reveal key qualitative differences between Rag paralogues in the regulation of mTORC1, and underscore Rag gene duplication and diversification as a potentially impactful event in mammalian evolution.

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Section: Discussionsupporting

confidence: 68%

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids

et al. 2022

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“…Although patients with familial DEPDC5‐related epilepsy harbor a germline mutation, they primarily present with focal pathology in the brain 13,14 . Genetic evidence has emerged that the focal pathology is the consequence of a pathogenic germline mutation and a somatic mutation leading to mosaic biallelic DEPDC5 loss‐of‐function (LOF), 39–41 concordant with Knudson's “2‐hit” hypothesis 42 .…”

Section: Discussionmentioning

confidence: 91%

“…For example, DEPDC5 variants were found in approximately 10% of cases in a retrospective SUDEP cohort 10 . In contrast to channelopathies, DEPDC5 ‐related epilepsy primarily manifests as a focal lesion in the brain 13,14 . Whereas patients with tuberous sclerosis complex (TSC), the prototypical monogenic disorder of the mTOR pathway, develop widespread developmental lesions in the brain and other organ systems (eg, skin, heart, and kidneys), 15 patients with DEPDC5 ‐related epilepsy have no extra‐neural lesions 13,14 .…”

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confidence: 99%

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Kao,

Yao,

Yang

et al. 2023

Annals of Neurology

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ObjectivesDEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5‐related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions.MethodsDepdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. EEG, cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice.ResultsDepdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non‐fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these animals developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole.InterpretationDepdc5 deletion in excitatory neurons is sufficient to cause DEPDC5‐related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5‐related epilepsy and SUDEP.This article is protected by copyright. All rights reserved.

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“…This is surprising as PI3K is a well-known enhancer of both MTORC1 substrates (Hay and Sonenberg, 2004). Recent evidence shows that the RAG GTPases mediate MTORC1 substrate specificity towards TFEB/TFE (Alesi et al, 2021; Figlia et al, 2022; Gollwitzer et al, 2022; Li et al, 2022; Napolitano et al, 2020), but no differential effect towards RPS6KB1 versus EIF4EBP1 has been described so far. The difference in EIF4EBP1 and RPS6KB1 phosphorylation may be explained by the higher affinity of EIF4EBP1 to the MTORC1 scaffold protein RAPTOR (Bohm et al, 2021; Fumagalli and Pende, 2022), which along with increased EIF4EBP1 levels may enhance recruitment and phosphorylation by MTORC1.…”

Section: Discussionmentioning

confidence: 99%

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

Pfänder

Hensen

Navas

et al. 2023

Preprint

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Limited supply and catabolism restrict the essential amino acid tryptophan (Trp) in tumors. How tumors sustain translation under Trp stress remains unclear. Unlike other amino acids, Trp stress activates the EGFR, which enhances macropinocytosis and RAS signaling to the MTORC1 and p38/MAPK kinases, sustaining translation. The AHR forms part of the Trp stress proteome and promotes autophagy to sustain Trp levels, and ceramide biosynthesis. Thus, Trp restriction elicits pro-translation signals enabling adaptation to nutrient stress, placing Trp into a unique position in the amino acid-mediated stress response. Our findings challenge the current perception that Trp restriction inhibits MTORC1 and the AHR and explain how both cancer drivers remain active. A glioblastoma patient subgroup with enhanced MTORC1 and AHR displays an autophagy signature, highlighting the clinical relevance of MTORC1-AHR crosstalk. Regions of high Trp or high ceramides are mutually exclusive, supporting that low Trp activates the EGFR-MTORC1-AHR axis in glioblastoma tissue.

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Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition

Cited by 15 publications

References 75 publications

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

The MTORC1-AHR pathway sustains translation and autophagy in tumours under tryptophan stress

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