raga-1 encodes the sole Caenorhabditis elegans orthologue of the RagA/RagB Rag GTPases (yeast Gtr1). RAGA-1 is a GTR/RAG-family GTP-binding protein that is predicted to form a heterodimer with RAGC-1 (RagC/D) on the lysosomal surface. There, in its GTP-bound state, it couples nutrient availability to activation of TORC1. In worms, depleting RAGA-1 lowers phosphorylation of the TORC1 target RSKS-1/S6K, and an endogenous GTP-locked Q63L allele raises it. Loss of raga-1 extends lifespan in a TOR-, DAF-16- and SKN-1-dependent manner, slows age-related locomotor decline, reduces body size and blunts the lifespan response to dietary restriction. Activated RAGA-1 restores larval growth in intestinal-sphingolipid-deficient animals. These organismal effects are downstream consequences of its role as a TORC1 activator.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003924 GTPase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GTPase activity inferred phylogenetically from yeast Gtr1/Gtr2 and mammalian RagA-D. RAGA-1 is a GTR/RAG family member with the Gtr1_RagA domain. Reason: RAGA-1 belongs to the GTR/RAG family and, like RagA/B, works as a nucleotide-state switch. The worm T18N (GDP-locked) and Q63L (GTP-locked) mutants give opposite phenotypes. GTP hydrolysis has not been measured for the worm protein, but the PAINT node covers the whole RagA/B clade and nothing suggests the worm protein lost it. Supporting Evidence: file:worm/raga-1/raga-1-uniprot.txt Belongs to the GTR/RAG GTP-binding protein family. file:worm/raga-1/raga-1-uniprot.txt Pfam; PF04670; Gtr1_RagA; 1. PMID:20523893 we made corresponding DN (T18N in C. elegans raga-1) and GF (Q63L) mutations in worm raga-1 |
| GO:0005525 GTP binding | IBA GO_REF:0000033 | ACCEPT | Summary: GTP binding inferred from the RagA/B clade. Reason: The Gtr1_RagA domain with an intact P-loop (GKSGSGKT at residues 11-18) and the opposite effects of the T18N and Q63L nucleotide-state mutants both support GTP binding as part of the core switch function. Supporting Evidence: file:worm/raga-1/raga-1-uniprot.txt Pfam; PF04670; Gtr1_RagA; 1. PMID:20523893 we made corresponding DN (T18N in C. elegans raga-1) and GF (Q63L) mutations in worm raga-1 |
| GO:0005525 GTP binding | IEA GO_REF:0000120 | ACCEPT | Summary: GTP binding from the combined automated pipeline (InterPro IPR006762, UniRule). Same claim as the IBA row. Reason: Same claim as the IBA GTP binding row and kept consistent with it; the Gtr1_RagA domain match is valid family-level support. Supporting Evidence: file:worm/raga-1/raga-1-uniprot.txt Pfam; PF04670; Gtr1_RagA; 1. file:worm/raga-1/raga-1-uniprot.txt Belongs to the GTR/RAG GTP-binding protein family. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear location inferred from yeast Gtr1/Gtr2 and human Rag proteins. Reason: No worm localization data exist for RAGA-1. The nuclear pool of Rag/Gtr proteins in yeast and mammals is minor and not where TORC1 activation happens. The inference is not contradicted, but it is peripheral to the core function, so it is kept as non-core. Supporting Evidence: PMID:20523893 raga-1 is the sole worm orthologue of the evolutionarily conserved ras-related GTPase RagA |
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: Lysosomal location inferred from mammalian RagA-D (lysosomal surface via Ragulator). Reason: Root organelle term (policy in projects/ORGANELLES.md). The IBA rests on mammalian RagA/B/C/D, which sit on the cytosolic face of the lysosome. That is where they recruit TORC1, and worm papers describe RAGA-1 in that frame. The organelle claim holds for the clade. There is no worm-specific localization, so only one line (orthology) supports a lysosomal-membrane sub-compartment, and no sub-compartment row is added. Supporting Evidence: PMID:20523893 raga-1 is the sole worm orthologue of the evolutionarily conserved ras-related GTPase RagA PMID:40385374 act as nutrient sensors that facilitate mTORC1 localization to lysosomes |
| GO:0008340 determination of adult lifespan | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: IGI with daf-2: raga-1(ok386) further extended lifespan of daf-2(e1368). Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. Supporting Evidence: PMID:20523893 raga-1(ok386) lifespan was extended even further in combination with e1368 |
| GO:0008340 determination of adult lifespan | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: IGI with daf-16: raga-1 lifespan extension depends on daf-16. Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. Supporting Evidence: PMID:20523893 raga-1 lifespan extension is dependent on daf-16 |
| GO:0008340 determination of adult lifespan | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: IGI with skn-1: skn-1 mutation reverses raga-1(ok386) lifespan extension. Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. Supporting Evidence: PMID:20523893 a skn-1 mutation reversed the lifespan extension of raga-1(ok386) |
| GO:0008340 determination of adult lifespan | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: IGI with rsks-1: raga-1(ok386) further extends rsks-1(ok1255) lifespan. Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. Supporting Evidence: PMID:20523893 In double mutants, raga-1(ok386) further increased rsks-1(ok1255) lifespan |
| GO:0008340 determination of adult lifespan | IMP PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: raga-1 deletion alleles and a dominant-negative transgene extend lifespan; wild-type raga-1 rescues. Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. Supporting Evidence: PMID:20523893 raga-1(ok386) showed increased lifespan across multiple survival analyses PMID:20523893 expression of wild-type raga-1 under its own promoter in the raga-1(ok386) background rescued lifespan to N2 lengths |
| GO:0008340 determination of adult lifespan | IMP PMID:22560223 TOR signaling and rapamycin influence longevity by regulatin... | KEEP AS NON CORE | Summary: Adult-only RNAi of TORC1 pathway genes, including the Rag GTPases, extends lifespan in a SKN-1- and DAF-16-dependent way. Reason: Lifespan is an organismal outcome of reduced TORC1 activity, not an activity of RAGA-1 itself, so this is kept as non-core. All determination of adult lifespan rows are treated alike. The full text states that raga-1 and ragc-1 were knocked down only during adulthood as TORC1 pathway genes, and that the lifespan increase from raga-1 RNAi depends on SKN-1 and DAF-16, consistent with the curator's IMP. Supporting Evidence: PMID:22560223 when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity PMID:22560223 Lifespan of the skn-1; daf-16 mutant was unaffected by raga-1 RNAi |
| GO:0009267 cellular response to starvation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cellular response to starvation, propagated from yeast, fly and mammalian Rag/Gtr proteins. Reason: The Rag heterodimer links nutrient (amino acid) availability to TORC1. In worms, raga-1(ok386) has a blunted lifespan response to food concentration. The term is a fair description of the clade's role in sensing nutrient withdrawal, but no worm assay shows a cellular starvation response, and no more specific worm-supported descendant exists. Kept as non-core. Supporting Evidence: PMID:20523893 raga-1(ok386) responses to dietary restriction were strongly blunted in comparison to wild-type N2 |
| GO:0010507 negative regulation of autophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Negative regulation of autophagy, propagated from yeast Gtr1/Gtr2 and mammalian RagA. Reason: Autophagy suppression is a downstream output of TORC1, which RAGA-1 activates. The Rag TORC1-activating step is the core function; the effect on autophagy is indirect. In PMID:22560223 the LGG-1 autophagy readout was reported for ragc-1 and daf-15 RNAi, not for raga-1; that RAGA-1 loss would likewise raise autophagy is an inference from its obligate RAGA-1/RAGC-1 heterodimer, not a result shown for raga-1. Kept as non-core. Supporting Evidence: PMID:40385374 leading to increased autophagy, decreased protein synthesis, and extended lifespan |
| GO:0032008 positive regulation of TOR signaling | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | MODIFY | Summary: IGI with let-363 (TOR): TOR RNAi extends lifespan of raga-1(GF) animals but not of raga-1(ok386) animals. Reason: The epistasis places raga-1 upstream of TOR, but TOR signaling is more general than the evidence supports. The worm data, including phospho-RSKS-1 readouts and use of RAGA-1 as a TORC1 activator, point to TORC1 specifically. Replace with positive regulation of TORC1 signaling (GO:1904263), a term the gene already carries (IBA). Proposed replacements: positive regulation of TORC1 signaling Supporting Evidence: PMID:20523893 While raga-1(GF) exhibited increased lifespan with TOR RNAi treatment compared to empty vector, raga-1(ok386) did not. This suggests that, as in other systems, raga-1 is acting through TOR to exert its effects on lifespan. PMID:37721956 As expected, somatic AID of RAGA-1 or LET-363 resulted in decreased levels of phosphorylated RSKS-1 |
| GO:0040018 positive regulation of multicellular organism growth | IMP PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | KEEP AS NON CORE | Summary: raga-1(ok386) adults are smaller than wild type. Reason: Body size is an organismal consequence of reduced TORC1 activity during larval growth. The GF transgene also gives small animals, so the size effect is not a simple dose readout of RAGA-1 activity. It is kept as non-core and not promoted to a core function. Supporting Evidence: PMID:20523893 On day one raga-1(ok386) adults were smaller than wild-type |
| GO:1904263 positive regulation of TORC1 signaling | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of TORC1 signaling, propagated across the RagA/B clade; this is the core biological role of RAGA-1. Reason: Worm biochemistry supports the IBA. Somatic degradation of RAGA-1 lowers phospho-RSKS-1 (S6K), and the endogenous GTP-locked Q63L allele raises it. Genetic epistasis places raga-1 upstream of TOR. Supporting Evidence: PMID:37721956 As expected, somatic AID of RAGA-1 or LET-363 resulted in decreased levels of phosphorylated RSKS-1 PMID:40385374 indicating that only the endogenous mutation is sufficient to increase mTORC1 activity PMID:20523893 While raga-1(GF) exhibited increased lifespan with TOR RNAi treatment compared to empty vector, raga-1(ok386) did not. This suggests that, as in other systems, raga-1 is acting through TOR to exert its effects on lifespan. |
| GO:1990131 Gtr1-Gtr2 GTPase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Membership of the Gtr1-Gtr2 (RagA/B-RagC/D) GTPase heterodimer, inferred from yeast, fission yeast and human. Reason: The worm genome encodes a single RagA/B (RAGA-1) and a single RagC/D (RAGC-1). Rag GTPases function only as A/B-C/D heterodimers in the characterized species. Physical association has not been shown for the worm proteins, but the PAINT clade assignment is sound. Supporting Evidence: PMID:40385374 In mammals, RagA/B and RagC/D form obligate heterodimers, while PMID:20523893 raga-1 is the sole worm orthologue of the evolutionarily conserved ras-related GTPase RagA |
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Download this section (compressed HTML)Q: Does C. elegans RAGA-1 bind and hydrolyse GTP with RagA-like kinetics, and is its nucleotide state controlled by worm GATOR1 (NPRL-2/NPRL-3) acting as a GAP?
Q: Which nutrient signals (amino acids, the sphingolipid d17iso-GlcCer, others) change the RAGA-1 nucleotide state in vivo, and does RAGA-1 itself respond to the lipid or act only as a permissive TORC1 activator?
Q: Why does the egIs12 raga-1(Q63L) transgene shorten lifespan without raising phospho-RSKS-1, while the endogenous Q63L allele raises phospho-RSKS-1 without shortening lifespan?
Experiment: Image endogenously tagged RAGA-1 and RAGC-1 together with lysosomal markers in fed and starved animals, and test their co-immunoprecipitation.
Hypothesis: RAGA-1 forms a heterodimer with RAGC-1 and is enriched on lysosomes in a nutrient-independent way, as RagA/B is in mammals.
Type: Live imaging and co-immunoprecipitation
Experiment: Measure GTP binding and hydrolysis by recombinant RAGA-1 (wild type, T18N, Q63L) alone and with RAGC-1 and worm NPRL-2/3.
Hypothesis: RAGA-1 has the low intrinsic GTPase activity typical of RagA, stimulated by GATOR1 orthologues.
Type: In vitro biochemistry
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Download this section (compressed HTML)raga-1 encodes the C. elegans ortholog of the ras-related GTPase RagA; in C. elegans RAGA-1 functions as a modifier of behavioral aging and adult lifespan (particularly under high food concentration); raga-1 mutations also affect body size and reproduction; genetic analyses suggest that raga-1 functions in the let-363/Tor pathway to regulate behavioral aging and lifespan and also interacts with the daf-2/daf-16 insulin signaling pathway and skn-1; raga-1 reporter fusions are widely expressed in larvae, with more restricted expression (gut, head and tail neurons, somatic gonad, hypodermis) seen in adults.
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