Journal articles: 'Rag GTPase'

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Shen, Kuang, and David M. Sabatini. "Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms." Proceedings of the National Academy of Sciences 115, no. 38 (September 4, 2018): 9545–50. http://dx.doi.org/10.1073/pnas.1811727115.

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The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique “locking” mechanism to stabilize its active (GTPRagA–RagCGDP) or inactive (GDPRagA–RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.

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Lee, Minji, Jong Hyun Kim, Ina Yoon, Chulho Lee, Mohammad Fallahi Sichani, Jong Soon Kang, Jeonghyun Kang, et al. "Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway." Proceedings of the National Academy of Sciences 115, no. 23 (May 21, 2018): E5279—E5288. http://dx.doi.org/10.1073/pnas.1801287115.

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A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating “ON” switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an “OFF” switch by controlling GTP hydrolysis of RagB in the Rag GTPase–mTORC1 axis. The LRS–RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP–GDP cycle of the RagD–RagB pair, rather than the RagC–RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD–RagB pair can overcome the absence of the RagC–RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD–RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.

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Gollwitzer, Peter, Nina Grützmacher, Sabine Wilhelm, Daniel Kümmel, and Constantinos Demetriades. "A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids." Nature Cell Biology 24, no. 9 (September 2022): 1394–406. http://dx.doi.org/10.1038/s41556-022-00976-y.

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AbstractAmino 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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Rogala, Kacper B., Xin Gu, Jibril F. Kedir, Monther Abu-Remaileh, Laura F. Bianchi, Alexia M. S. Bottino, Rikke Dueholm, et al. "Structural basis for the docking of mTORC1 on the lysosomal surface." Science 366, no. 6464 (October 10, 2019): 468–75. http://dx.doi.org/10.1126/science.aay0166.

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The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)–Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP–RagC/D•GDP) permits mTORC1 association. We used cryo–electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms. Our findings indicate that the Raptor α-solenoid directly detects the nucleotide state of RagA while the Raptor “claw” threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we developed a model of active mTORC1 docked on the lysosome.

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Figlia, Gianluca, Sandra Müller, Anna M. Hagenston, Susanne Kleber, Mykola Roiuk, Jan-Philipp Quast, Nora ten Bosch, et al. "Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition." Nature Cell Biology 24, no. 9 (September 2022): 1407–21. http://dx.doi.org/10.1038/s41556-022-00977-x.

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AbstractMechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to appropriately regulate cellular anabolism and catabolism. During nutrient restriction, different organs in an animal do not respond equally, with vital organs being relatively spared. This raises the possibility that mTORC1 is differentially regulated in different cell types, yet little is known about this mechanistically. The Rag GTPases, RagA or RagB bound to RagC or RagD, tether mTORC1 in a nutrient-dependent manner to lysosomes where mTORC1 becomes activated. Although the RagA and B paralogues were assumed to be functionally equivalent, we find here that the RagB isoforms, which are highly expressed in neurons, impart mTORC1 with resistance to nutrient starvation by inhibiting the RagA/B GTPase-activating protein GATOR1. We further show that high expression of RagB isoforms is observed in some tumours, revealing an alternative strategy by which cancer cells can retain elevated mTORC1 upon low nutrient availability.

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Anandapadamanaban, Madhanagopal, Glenn R. Masson, Olga Perisic, Alex Berndt, Jonathan Kaufman, Chris M. Johnson, Balaji Santhanam, Kacper B. Rogala, David M. Sabatini, and Roger L. Williams. "Architecture of human Rag GTPase heterodimers and their complex with mTORC1." Science 366, no. 6462 (October 10, 2019): 203–10. http://dx.doi.org/10.1126/science.aax3939.

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The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo–electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.

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Zhu, Min, and Xiu-qi Wang. "Regulation of mTORC1 by Small GTPases in Response to Nutrients." Journal of Nutrition 150, no. 5 (January 21, 2020): 1004–11. http://dx.doi.org/10.1093/jn/nxz301.

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ABSTRACT Mechanistic target of rapamycin complex 1 (mTORC1) is a highly evolutionarily conserved serine/threonine kinase that regulates cell growth and metabolism in response to multiple environmental cues, such as nutrients, hormones, energy, and stress. Deregulation of mTORC1 can lead to diseases such as diabetes, obesity, and cancer. A series of small GTPases, including Rag, Ras homolog enriched in brain (Rheb), adenosine diphosphate ribosylation factor 1 (Arf1), Ras-related protein Ral-A, Ras homolog (Rho), and Rab, are involved in regulating mTORC1 in response to nutrients, and mTORC1 is differentially regulated via these small GTPases according to specific conditions. Leucine and arginine sensing are considered to be well-confirmed amino acid–sensing signals, activating mTORC1 via a Rag GTPase–dependent mechanism as well as the Ragulator complex and vacuolar H+-adenosine triphosphatase (v-ATPase). Glutamine promotes mTORC1 activation via Arf1 independently of the Rag GTPase. In this review, we summarize current knowledge regarding the regulation of mTORC1 activity by small GTPases in response to nutrients, focusing on the function of small GTPases in mTORC1 activation and how small GTPases are regulated by nutrients.

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Meng, Delong, Qianmei Yang, Huanyu Wang, Chase H. Melick, Rishika Navlani, Anderson R. Frank, and Jenna L. Jewell. "Glutamine and asparagine activate mTORC1 independently of Rag GTPases." Journal of Biological Chemistry 295, no. 10 (February 4, 2020): 2890–99. http://dx.doi.org/10.1074/jbc.ac119.011578.

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Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed, human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase–independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.

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Zhu, Xingxing, Xian Zhou, Chaofan Li, Yanfeng Li, Jie Sun, Ariel Raybuck, Mark Robin Boothby, and Hu Zeng. "Rag GTPase critically contributes to humoral immunity independent of canonical mTORC1 signaling." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 112.03. http://dx.doi.org/10.4049/jimmunol.208.supp.112.03.

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Abstract The humoral immune response requires that B cells undergo a rapid metabolic shift and high demand of nutrients, which are vital to sustain the formation of germinal center. Rag GTPase senses amino acid availability to activate mechanistic target of rapamycin complex 1(mTORC1) pathway and modulate the function of transcription factor EB (TFEB), a member of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, little is known about how Rag GTPase coordinates amino acid sensing, mTORC1 activation and TFEB activity in humoral immune response. Here, we show that B cell intrinsic Rag GTPase is critical to the development and activation of B cells. Disruption of Rag GTPase complex, but not mTORC1 complex, abrogates germinal center formation, antibody production as well as plasma cell generation upon respiratory influenza infection. Mechanistically, the Rag GTPase complex senses specific amino acids to suppress TFEB activity, independent of canonical mTORC1 activation. Collectively, our data support the idea that Rag GTPase critically contributes to humoral immunity partly through suppressing TFEB and it is largely not necessary for canonical mTORC1 signaling. Supported by Mayo Foundation for Medical Education and Research

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Petit, Constance S., Agnes Roczniak-Ferguson, and Shawn M. Ferguson. "Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases." Journal of Cell Biology 202, no. 7 (September 30, 2013): 1107–22. http://dx.doi.org/10.1083/jcb.201307084.

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Birt-Hogg-Dubé syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid–stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. FLCN-interacting protein 1 (FNIP1) promotes both the lysosome recruitment and Rag interactions of FLCN. These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid–dependent activation of mTOR via its direct interaction with the RagA/B GTPases.

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Meng, Jin, and Shawn M. Ferguson. "GATOR1-dependent recruitment of FLCN–FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids." Journal of Cell Biology 217, no. 8 (May 30, 2018): 2765–76. http://dx.doi.org/10.1083/jcb.201712177.

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Folliculin (FLCN) is a tumor suppressor that coordinates cellular responses to changes in amino acid availability via regulation of the Rag guanosine triphosphatases. FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). The FLCN–FNIP heterodimer also has GTPase-activating protein (GAP) activity toward RagC/D. These properties raised two important questions. First, how is amino acid availability sensed to regulate lysosomal abundance of FLCN? Second, what is the relationship between FLCN lysosome localization, RagA/B interactions, and RagC/D GAP activity? In this study, we show that RagA/B nucleotide status determines the FLCN–FNIP1 recruitment to lysosomes. Starvation-induced FLCN–FNIP lysosome localization requires GAP activity toward Rags 1 (GATOR1), the GAP that converts RagA/B to the guanosine diphosphate (GDP)-bound state. This places FLCN–FNIP recruitment to lysosomes under the control of amino acid sensors that act upstream of GATOR1. By binding to RagA/BGDP and acting on RagC/D, FLCN–FNIP can coordinate nucleotide status between Rag heterodimer subunits in response to changes in amino acid availability.

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Sancak, Yasemin, and David M. Sabatini. "Rag proteins regulate amino-acid-induced mTORC1 signalling." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 289–90. http://dx.doi.org/10.1042/bst0370289.

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The serum- and nutrient-sensitive protein kinase mTOR (mammalian target of rapamycin) is a master regulator of cell growth and survival. The mechanisms through which nutrients regulate mTOR have been one of the major unanswered questions in the mTOR field. Identification of the Rag (Ras-related GTPase) family of GTPases as mediators of amino acid signalling to mTOR is an important step towards our understanding of this mechanism.

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Amemiya, Yuna, Nao Nakamura, Nao Ikeda, Risa Sugiyama, Chiaki Ishii, Masatoshi Maki, Hideki Shibata, and Terunao Takahara. "Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin." International Journal of Molecular Sciences 22, no. 13 (June 27, 2021): 6897. http://dx.doi.org/10.3390/ijms22136897.

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Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Here we report that amino acids also converge on regulation of the TSC2-Rheb GTPase axis via Ca2+/calmodulin (CaM). We showed that the amino acid-mediated increase of intracellular Ca2+ is important for mTORC1 activation and thereby contributes to the promotion of nascent protein synthesis. We found that Ca2+/CaM interacted with TSC2 at its GTPase activating protein (GAP) domain and that a CaM inhibitor reduced binding of CaM with TSC2. The inhibitory effect of a CaM inhibitor on mTORC1 activity was prevented by loss of TSC2 or by an active mutant of Rheb GTPase, suggesting that a CaM inhibitor acts through the TSC2-Rheb axis to inhibit mTORC1 activity. Taken together, in response to amino acids, Ca2+/CaM-mediated regulation of the TSC2-Rheb axis contributes to proper mTORC1 activation, in addition to the well-known lysosomal translocation of mTORC1 by Rag GTPases.

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Kim, Joungmok, and Eunjung Kim. "Rag GTPase in amino acid signaling." Amino Acids 48, no. 4 (January 18, 2016): 915–28. http://dx.doi.org/10.1007/s00726-016-2171-x.

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Schlingmann, Karl P., François Jouret, Kuang Shen, Anukrati Nigam, Francisco J. Arjona, Claudia Dafinger, Pascal Houillier, et al. "mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy." Journal of the American Society of Nephrology 32, no. 11 (October 4, 2021): 2885–99. http://dx.doi.org/10.1681/asn.2021030333.

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BackgroundOver the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis.MethodsWe performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase).ResultsIn eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro.ConclusionsOur findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

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Jung, Jennifer, Heide Marika Genau, and Christian Behrends. "Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9." Molecular and Cellular Biology 35, no. 14 (May 11, 2015): 2479–94. http://dx.doi.org/10.1128/mcb.00125-15.

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The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Depletion of SLC38A9 inhibits mTORC1 activity in the presence of amino acids and in response to amino acid replenishment following starvation. Conversely, SLC38A9 overexpression causes RHEB (Ras homolog enriched in brain) GTPase-dependent hyperactivation of mTORC1 and partly sustains mTORC1 activity upon amino acid deprivation. Intriguingly, during amino acid starvation mTOR is retained at the lysosome upon SLC38A9 depletion but fails to be activated. Together, the findings of our study reveal SLC38A9 as a Rag-Ragulator complex member transducing amino acid availability to mTORC1 activity.

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Hesketh, Geoffrey G., Fotini Papazotos, Judy Pawling, Dushyandi Rajendran, James D. R. Knight, Sebastien Martinez, Mikko Taipale, Daniel Schramek, James W. Dennis, and Anne-Claude Gingras. "The GATOR–Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids." Science 370, no. 6514 (October 15, 2020): 351–56. http://dx.doi.org/10.1126/science.aaz0863.

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The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR–Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase–independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.

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Laufenberg, Lacee J., Kristen T. Crowell, and Charles H. Lang. "Alcohol Acutely Antagonizes Refeeding-Induced Alterations in the Rag GTPase-Ragulator Complex in Skeletal Muscle." Nutrients 13, no. 4 (April 9, 2021): 1236. http://dx.doi.org/10.3390/nu13041236.

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The Ragulator protein complex is critical for directing the Rag GTPase proteins and mTORC1 to the lysosome membrane mediating amino acid-stimulated protein synthesis. As there is a lack of evidence on alcohol’s effect on the Rag-Ragulator complex as a possible mechanism for the development of alcoholic skeletal muscle wasting, the aim of our study was to examine alterations in various protein–protein complexes in the Rag-Ragulator pathway produced acutely by feeding and how these are altered by alcohol under in vivo conditions. Mice (C57Bl/6; adult males) were fasted, and then provided rodent chow for 30 min (“refed”) or remained food-deprived (“fasted”). Mice subsequently received ethanol (3 g/kg ethanol) or saline intraperitoneally, and hindlimb muscles were collected 1 h thereafter for analysis. Refeeding-induced increases in myofibrillar and sarcoplasmic protein synthesis, and mTOR and S6K1 phosphorylation, were prevented by alcohol. This inhibition was not associated with a differential rise in the intracellular leucine concentration or plasma leucine or insulin levels. Alcohol increased the amount of the Sestrin1•GATOR2 complex in the fasted state and prevented the refeeding-induced decrease in Sestrin1•GATOR2 seen in control mice. Alcohol antagonized the increase in the RagA/C•Raptor complex formation seen in the refed state. Alcohol antagonized the increase in Raptor with immunoprecipitated LAMPTOR1 (part of the Ragulator complex) after refeeding and decreased the association of RagC with LAMPTOR1. Finally, alcohol increased the association of the V1 domain of v-ATPase with LAMPTOR1 and prevented the refeeding-induced decrease in v-ATPase V1 with LAMPTOR1. Overall, these data demonstrate that acute alcohol intake disrupts multiple protein–protein complexes within the Rag-Ragulator complex, which are associated with and consistent with the concomitant decline in nutrient-stimulated muscle protein synthesis under in vivo conditions.

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Lawrence, Rosalie E., Simon A. Fromm, Yangxue Fu, Adam L. Yokom, Do Jin Kim, Ashley M. Thelen, Lindsey N. Young, et al. "Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex." Science 366, no. 6468 (October 31, 2019): 971–77. http://dx.doi.org/10.1126/science.aax0364.

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The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo–electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.

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Jansen, Rachel M., Adam Yokom, Simon Fromm, and James H. Hurley. "Structural insights into Rag gtpase activation by FLCN:FNIP2." Biophysical Journal 121, no. 3 (February 2022): 39a—40a. http://dx.doi.org/10.1016/j.bpj.2021.11.2504.

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Nicastro, Raffaele, Alessandro Sardu, Nicolas Panchaud, and Claudio De Virgilio. "The Architecture of the Rag GTPase Signaling Network." Biomolecules 7, no. 4 (June 30, 2017): 48. http://dx.doi.org/10.3390/biom7030048.

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Hatakeyama, Riko, and Claudio De Virgilio. "Unsolved mysteries of Rag GTPase signaling in yeast." Small GTPases 7, no. 4 (August 15, 2016): 239–46. http://dx.doi.org/10.1080/21541248.2016.1211070.

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Hong-Brown, Ly Q., C. Randell Brown, Abid A. Kazi, Maithili Navaratnarajah, and Charles H. Lang. "Rag GTPases and AMPK/TSC2/Rheb mediate the differential regulation of mTORC1 signaling in response to alcohol and leucine." American Journal of Physiology-Cell Physiology 302, no. 10 (May 15, 2012): C1557—C1565. http://dx.doi.org/10.1152/ajpcell.00407.2011.

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Leucine (Leu) and insulin both stimulate muscle protein synthesis, albeit at least in part via separate signaling pathways. While alcohol (EtOH) suppresses insulin-stimulated protein synthesis in cultured myocytes, its ability to disrupt Leu signaling and Rag GTPase activity has not been determined. Likewise, little is known regarding the interaction of EtOH and Leu on the AMPK/TSC2/Rheb pathway. Treatment of myocytes with EtOH (100 mM) decreased protein synthesis, whereas Leu (2 mM) increased synthesis. In combination, EtOH suppressed the anabolic effect of Leu. The effects of EtOH and Leu were associated with coordinate changes in the phosphorylation state of mTOR, raptor, and their downstream targets 4EBP1 and S6K1. As such, EtOH suppressed the ability of Leu to activate these signaling components. The Rag signaling pathway was activated by Leu but suppressed by EtOH, as evidenced by changes in the interaction of Rag proteins with mTOR and raptor. Overexpression of constitutively active (ca)RagA and caRagC increased mTORC1 activity, as determined by increased S6K1 phosphorylation. Furthermore, the caRagA-caRagC heterodimer blocked the inhibitory effect of EtOH. EtOH and Leu produced differential effects on AMPK signaling. EtOH enhanced AMPK activity, resulting in increased TSC2 (S1387) and eEF2 phosphorylation, whereas Leu had the opposite effect. EtOH also decreased the interaction of Rheb with mTOR, and this was prevented by Leu. Collectively, our results indicate that EtOH inhibits the anabolic effects that Leu has on protein synthesis and mTORC1 activity by modulating both Rag GTPase function and AMPK/TSC2/Rheb signaling.

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Schreiber, Matthew A., Jonathan T. Pierce-Shimomura, Stefan Chan, Dianne Parry, and Steven L. McIntire. "Manipulation of Behavioral Decline in Caenorhabditis elegans with the Rag GTPase raga-1." PLoS Genetics 6, no. 5 (May 27, 2010): e1000972. http://dx.doi.org/10.1371/journal.pgen.1000972.

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Gu, Xin, Jose M. Orozco, Robert A. Saxton, Kendall J. Condon, Grace Y. Liu, Patrycja A. Krawczyk, Sonia M. Scaria, J. Wade Harper, Steven P. Gygi, and David M. Sabatini. "SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway." Science 358, no. 6364 (November 9, 2017): 813–18. http://dx.doi.org/10.1126/science.aao3265.

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mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.

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Avruch, Joseph, Xiaomeng Long, Sara Ortiz-Vega, Joseph Rapley, Angela Papageorgiou, and Ning Dai. "Amino acid regulation of TOR complex 1." American Journal of Physiology-Endocrinology and Metabolism 296, no. 4 (April 2009): E592—E602. http://dx.doi.org/10.1152/ajpendo.90645.2008.

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TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GβL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3′OH-phosphatidylinositol, in this process is unclear.

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Mohanasundaram, Ponnuswamy, Leila S. Coelho-Rato, Mayank Kumar Modi, Marta Urbanska, Franziska Lautenschläger, Fang Cheng, and John E. Eriksson. "Cytoskeletal vimentin regulates cell size and autophagy through mTORC1 signaling." PLOS Biology 20, no. 9 (September 13, 2022): e3001737. http://dx.doi.org/10.1371/journal.pbio.3001737.

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The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here, we show that vimentin, a cytoskeletal intermediate filament protein that we have known to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. This vimentin-mediated regulation is manifested at all levels of mTOR downstream target activation and protein synthesis. We found that vimentin maintains normal cell size by supporting mTORC1 translocation and activation by regulating the activity of amino acid sensing Rag GTPase. We also show that vimentin inhibits the autophagic flux in the absence of growth factors and/or critical nutrients, demonstrating growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings establish that vimentin couples cell size and autophagy through modulating Rag GTPase activity of the mTORC1 signaling pathway.

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Panchaud, N., M. P. Peli-Gulli, and C. De Virgilio. "Amino Acid Deprivation Inhibits TORC1 Through a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr1." Science Signaling 6, no. 277 (May 28, 2013): ra42. http://dx.doi.org/10.1126/scisignal.2004112.

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Péli-Gulli, Marie-Pierre, Alessandro Sardu, Nicolas Panchaud, Serena Raucci, and Claudio De Virgilio. "Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2." Cell Reports 13, no. 1 (October 2015): 1–7. http://dx.doi.org/10.1016/j.celrep.2015.08.059.

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Wróbel, Marta, Jarosław Cendrowski, Ewelina Szymańska, Malwina Grębowicz-Maciukiewicz, Noga Budick-Harmelin, Matylda Macias, Aleksandra Szybińska, et al. "ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway." Life Science Alliance 5, no. 7 (March 30, 2022): e202101239. http://dx.doi.org/10.26508/lsa.202101239.

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Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Here, we show that mammalian ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. The altered lysosome morphology upon ESCRT-I depletion coincided with elevated expression of genes annotated to biogenesis of lysosomes due to prolonged activation of TFEB/TFE3 transcription factors. Lack of ESCRT-I also induced transcription of cholesterol biosynthesis genes, in response to inefficient delivery of cholesterol from endolysosomal compartments. Among factors that could possibly activate TFEB/TFE3 signaling upon ESCRT-I deficiency, we excluded lysosomal cholesterol accumulation and Ca2+-mediated dephosphorylation of TFEB/TFE3. However, we discovered that this activation occurs due to the inhibition of Rag GTPase–dependent mTORC1 pathway that specifically reduced phosphorylation of TFEB at S112. Constitutive activation of the Rag GTPase complex in cells lacking ESCRT-I restored S112 phosphorylation and prevented TFEB/TFE3 activation. Our results indicate that ESCRT-I deficiency evokes a homeostatic response to counteract lysosomal nutrient starvation, that is, improper supply of nutrients derived from lysosomal degradation.

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Kim, Young-Mi, Matthew Stone, Tae Hyun Hwang, Yeon-Gil Kim, Jane R. Dunlevy, Timothy J. Griffin, and Do-Hyung Kim. "SH3BP4 Is a Negative Regulator of Amino Acid-Rag GTPase-mTORC1 Signaling." Molecular Cell 46, no. 6 (June 2012): 833–46. http://dx.doi.org/10.1016/j.molcel.2012.04.007.

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Kalender, Adem, Anand Selvaraj, So Young Kim, Pawan Gulati, Sophie Brûlé, Benoit Viollet, Bruce E. Kemp, et al. "Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner." Cell Metabolism 11, no. 5 (May 2010): 390–401. http://dx.doi.org/10.1016/j.cmet.2010.03.014.

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Fromm, Simon A., Rosalie E. Lawrence, and James H. Hurley. "Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9." Nature Structural & Molecular Biology 27, no. 11 (August 31, 2020): 1017–23. http://dx.doi.org/10.1038/s41594-020-0490-9.

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Cherfils, Jacqueline. "Encoding Allostery in mTOR Signaling: The Structure of the Rag GTPase/Ragulator Complex." Molecular Cell 68, no. 5 (December 2017): 823–24. http://dx.doi.org/10.1016/j.molcel.2017.11.027.

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Pu, Jing, Tal Keren-Kaplan, and Juan S. Bonifacino. "A Ragulator–BORC interaction controls lysosome positioning in response to amino acid availability." Journal of Cell Biology 216, no. 12 (October 9, 2017): 4183–97. http://dx.doi.org/10.1083/jcb.201703094.

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Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/threonine kinase from the lysosomal membrane. Decreased phosphorylation of mTORC1 substrates inhibits protein synthesis while activating autophagy. Amino acid depletion also causes clustering of lysosomes in the juxtanuclear area of the cell, but the mechanisms responsible for this phenomenon are poorly understood. Herein we show that Ragulator directly interacts with BLOC-1–related complex (BORC), a multi-subunit complex previously found to promote lysosome dispersal through coupling to the small GTPase Arl8 and the kinesins KIF1B and KIF5B. Interaction with Ragulator exerts a negative regulatory effect on BORC that is independent of mTORC1 activity. Amino acid depletion strengthens this interaction, explaining the redistribution of lysosomes to the juxtanuclear area. These findings thus demonstrate that amino acid availability controls lysosome positioning through Ragulator-dependent, but mTORC1-independent, modulation of BORC.

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Lawrence, Rosalie E., Kelvin F. Cho, Ronja Rappold, Anna Thrun, Marie Tofaute, Do Jin Kim, Ofer Moldavski, James H. Hurley, and Roberto Zoncu. "A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase–Ragulator lysosomal scaffold." Nature Cell Biology 20, no. 9 (July 30, 2018): 1052–63. http://dx.doi.org/10.1038/s41556-018-0148-6.

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37

Shen, Kuang, Abigail Choe, and David M. Sabatini. "Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability." Molecular Cell 68, no. 3 (November 2017): 552–65. http://dx.doi.org/10.1016/j.molcel.2017.09.026.

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Shen, Kuang, Abigail Choe, and David M. Sabatini. "Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability." Molecular Cell 68, no. 4 (November 2017): 821. http://dx.doi.org/10.1016/j.molcel.2017.10.031.

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Megat, Salim, Pradipta R. Ray, Jamie K. Moy, Tzu-Fang Lou, Paulino Barragán-Iglesias, Yan Li, Grishma Pradhan, et al. "Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain." Journal of Neuroscience 39, no. 3 (November 20, 2018): 393–411. http://dx.doi.org/10.1523/jneurosci.2661-18.2018.

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Oshiro, Noriko, Joseph Rapley, and Joseph Avruch. "Amino Acids Activate Mammalian Target of Rapamycin (mTOR) Complex 1 without Changing Rag GTPase Guanyl Nucleotide Charging." Journal of Biological Chemistry 289, no. 5 (December 11, 2013): 2658–74. http://dx.doi.org/10.1074/jbc.m113.528505.

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Ortega-Molina, Ana, Cristina Lebrero-Fernández, Alba Sanz, Nerea Deleyto-Seldas, Ana Belén Plata-Gómez, Camino Menéndez, Osvaldo Graña-Castro, Eduardo Caleiras, and Alejo Efeyan. "Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs." Cell Reports 36, no. 2 (July 2021): 109372. http://dx.doi.org/10.1016/j.celrep.2021.109372.

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Yang, Shu, Yingbiao Zhang, Chun-Yuan Ting, Lucia Bettedi, Kuikwon Kim, Elena Ghaniam, and Mary A. Lilly. "The Rag GTPase Regulates the Dynamic Behavior of TSC Downstream of Both Amino Acid and Growth Factor Restriction." Developmental Cell 55, no. 3 (November 2020): 272–88. http://dx.doi.org/10.1016/j.devcel.2020.08.006.

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Powis, Katie, Tianlong Zhang, Nicolas Panchaud, Rong Wang, Claudio De Virgilio, and Jianping Ding. "Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling." Cell Research 25, no. 9 (July 24, 2015): 1043–59. http://dx.doi.org/10.1038/cr.2015.86.

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Ortega-Molina, Ana, Nerea Deleyto-Seldas, Joaquim Carreras, Alba Sanz, Cristina Lebrero-Fernández, Camino Menéndez, Andrew Vandenberg, et al. "Oncogenic Rag GTPase signalling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR." Nature Metabolism 1, no. 8 (August 2019): 775–89. http://dx.doi.org/10.1038/s42255-019-0098-8.

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Péli-Gulli, Marie-Pierre, Serena Raucci, Zehan Hu, Jörn Dengjel, and Claudio De Virgilio. "Feedback Inhibition of the Rag GTPase GAP Complex Lst4-Lst7 Safeguards TORC1 from Hyperactivation by Amino Acid Signals." Cell Reports 20, no. 2 (July 2017): 281–88. http://dx.doi.org/10.1016/j.celrep.2017.06.058.

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Kim, Maengjo, Linghui Lu, Alexey V. Dvornikov, Xiao Ma, Yonghe Ding, Ping Zhu, Timothy M. Olson, Xueying Lin, and Xiaolei Xu. "TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy." International Journal of Molecular Sciences 22, no. 11 (May 23, 2021): 5494. http://dx.doi.org/10.3390/ijms22115494.

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A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR–TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition.

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Kvainickas, Arunas, Heike Nägele, Wenjing Qi, Ladislav Dokládal, Ana Jimenez-Orgaz, Luca Stehl, Dipak Gangurde, et al. "Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid–induced mTORC1 signaling." Journal of Cell Biology 218, no. 9 (August 20, 2019): 3019–38. http://dx.doi.org/10.1083/jcb.201812110.

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Retromer is an evolutionarily conserved multiprotein complex that orchestrates the endocytic recycling of integral membrane proteins. Here, we demonstrate that retromer is also required to maintain lysosomal amino acid signaling through mTORC1 across species. Without retromer, amino acids no longer stimulate mTORC1 translocation to the lysosomal membrane, which leads to a loss of mTORC1 activity and increased induction of autophagy. Mechanistically, we show that its effect on mTORC1 activity is not linked to retromer’s role in the recycling of transmembrane proteins. Instead, retromer cooperates with the RAB7-GAP TBC1D5 to restrict late endosomal RAB7 into microdomains that are spatially separated from the amino acid–sensing domains. Upon loss of retromer, RAB7 expands into the ragulator-decorated amino acid–sensing domains and interferes with RAG-GTPase and mTORC1 recruitment. Depletion of retromer in Caenorhabditis elegans reduces mTORC1 signaling and extends the lifespan of the worms, confirming an evolutionarily conserved and unexpected role for retromer in the regulation of mTORC1 activity and longevity.

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Pai, Sung-Yun, Chaekyun Kim, and David A. Williams. "Rac GTPases in Human Diseases." Disease Markers 29, no. 3-4 (2010): 177–87. http://dx.doi.org/10.1155/2010/380291.

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Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase,RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out ofRAC2and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.

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Kwon, Ohman, Dongoh Kwak, Sang Hoon Ha, Hyeona Jeon, Mangeun Park, Yeonho Chang, Pann-Ghill Suh, and Sung Ho Ryu. "Nudix-type motif 2 contributes to cancer proliferation through the regulation of Rag GTPase-mediated mammalian target of rapamycin complex 1 localization." Cellular Signalling 32 (April 2017): 24–35. http://dx.doi.org/10.1016/j.cellsig.2017.01.015.

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Tsukuba, Takayuki, Yu Yamaguchi, and Tomoko Kadowaki. "Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains." International Journal of Molecular Sciences 22, no. 14 (July 19, 2021): 7691. http://dx.doi.org/10.3390/ijms22147691.

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Rab GTPases are major coordinators of intracellular membrane trafficking, including vesicle transport, membrane fission, tethering, docking, and fusion events. Rab GTPases are roughly divided into two groups: conventional “small” Rab GTPases and atypical “large” Rab GTPases that have been recently reported. Some members of large Rab GTPases in mammals include Rab44, Rab45/RASEF, and Rab46. The genes of these large Rab GTPases commonly encode an amino-terminal EF-hand domain, coiled-coil domain, and the carboxyl-terminal Rab GTPase domain. A common feature of large Rab GTPases is that they express several isoforms in cells. For instance, Rab44’s two isoforms have similar functions, but exhibit differential localization. The long form of Rab45 (Rab45-L) is abundantly distributed in epithelial cells. The short form of Rab45 (Rab45-S) is predominantly present in the testes. Both Rab46 (CRACR2A-L) and the short isoform lacking the Rab domain (CRACR2A-S) are expressed in T cells, whereas Rab46 is only distributed in endothelial cells. Although evidence regarding the function of large Rab GTPases has been accumulating recently, there are only a limited number of studies. Here, we report the recent findings on the large Rab GTPase family concerning their function in membrane trafficking, cell differentiation, related diseases, and knockout mouse phenotypes.

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Journal articles on the topic 'Rag GTPase'

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