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Review
. 2024 Jul 10;15(1):5812.
doi: 10.1038/s41467-024-50034-4.

Ragopathies and the rising influence of RagGTPases on human diseases

Irene Sambri #  1   2 , Marco Ferniani #  3   4 , Andrea Ballabio  5   6   7   8
Affiliations
Review

Ragopathies and the rising influence of RagGTPases on human diseases

Irene Sambri et al. Nat Commun. .

Abstract

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators. The resulting phenotypes may encompass a variety of clinical features such as cataract, kidney tubulopathy, dilated cardiomyopathy and several types of cancer. In this review, we focus on the key clinical, molecular and physio-pathological features of ragopathies, aiming to shed light on their underlying mechanisms.

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Conflict of interest statement

A.B. is cofounder of CASMA Therapeutics, Inc, and Advisory board member of Avilar and Amplify Therapeutics. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Regulation of Rag GTPase Activity in the Presence or Absence of Amino Acids.
A Low nutrient condition: During nutrient deprivation, GATOR1, with its co-factor KICSTOR, promotes the GDP-loading of RagA/B, preventing the lysosomal recruitment of mTORC1. Conversely, nutrient deprivation promotes lysosomal recruitment of FLCN, which inhibits its GAP activity toward RagC/D. The resulting RagA/B-GDP;RagC/D-GTP heterodimers lead to mTORC1 inactivation and promote TFEB nuclear translocation. TFEB binds to CLEAR sequences found within the promoter of its target genes, exerting control over multiple pathways and cellular functions such as autophagy, lysosomal biogenesis, and mTORC1 signaling, the latter being controlled through the upregulation of RagC/D GTPases. B Nutrient rich condition: Nutrients in the lysosomal lumen inhibit GATOR1 and promote mTORC1 lysosomal recruitment through Rag-dependent mechanisms mediated by interaction between RagA/B with Raptor. This condition allows the activity of mTORC1 towards S6K and 4E-BP1 and activates the GAP activity of FLCN toward RagC/D, favoring their GDP-loading. The resulting RagA/B GTP–RagC/D-GDP heterodimers enable the recruitment of TFEB to mTORC1.Figure created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.
Fig. 2
Fig. 2. Diseases arising from genetic mutations in Rag GTPases and their regulators.
The figure provides a schematic representation of the organs primarily affected in conditions resulting from human mutations in the Rags and their regulators, highlighting the impact of their mutations on mTORC1 and TFEB activity. Gain of Function mutations in Rag GTPases: Germinal mutations in RRAGA are associated with cataracts, but the impact on mTORC1 and TFEB activity remains unexplored. Somatic mutations in RRAGC, which are linked to follicular lymphoma, lead to a modest increase in mTORC1 activity. Germline mutations in RRAGC, causing cardiomyopathies, (with possible additional features as brain cortical dysplasia, hepatic dysfunction or ocular abnormalities), result in the cytosolic sequestration of TFEB. Nevertheless, the effect on mTORC1 activity toward its canonical substrates appears to be only partially increased. Germline mutations in RRAGD do not affect canonical mTORC1 signaling but lead to cytosolic sequestration of TFEB. Loss of function mutations in Rag GTPases regulators: Germline or somatic mutations in GATOR1 subunits (DEPDC5, NPRL2/3) associated with epilepsy syndrome result in an upregulation of canonical mTORC1 signaling. Germline mutations in KICSTOR subunits (KPTN and SZT2), leading to neuro-developmental disorders, also cause an upregulation of canonical mTORC1 signaling. Germline and somatic mutations in Folliculin (FLCN) or PRDM10 are causative of Birt-Hogg-Dubé syndrome. These mutations result in an upregulation of canonical mTORC1 signaling and lead to a constitutively nuclear localization of TFEB. Figure created with BioRender.com, released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license.
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