let-363

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000492 box C/D snoRNP assembly	IMP PMID:18804378 The Target of Rapamycin pathway antagonizes pha-4/FoxA to co...	MARK AS OVER ANNOTATED	Summary: let-363 RNAi lowers FIB-1 levels and leaves FIB-1 in the nucleoplasm and nucleolar periphery instead of the nucleolus. Sheaffer et al. infer that CeTOR promotes box C/D snoRNP accumulation in nucleoli. Reason: The experiment measures FIB-1 abundance and nucleolar localization after TOR knockdown, a downstream readout of reduced growth signalling. Starvation produces the same change. LET-363 is a kinase acting upstream; nothing shows that it binds snoRNP components or does any step of snoRNP assembly. RUVB-1 is the protein in this paper with an assembly role. The annotation records an indirect effect of TOR signalling on ribosome biogenesis as direct participation in snoRNP assembly. GO has no 'regulation of box C/D snoRNP assembly' term (OLS search) to move it to. Supporting Evidence: PMID:18804378 Inactivation of let-363/TOR produced similar defects, with low levels of FIB-1, which were localized to the nucleoplasm and nucleolar periphery PMID:18804378 We analyzed worms that had undergone eight hours starvation and observed that FIB-1 levels were reduced and restricted to the nucleoplasm
GO:0002119 nematode larval development	IMP PMID:12150926 Raptor, a binding partner of target of rapamycin (TOR), medi...	KEEP AS NON CORE	Summary: let-363 loss of function (mutation or RNAi) causes larval arrest at mid-to-late L3, with gonadal degeneration and intestinal atrophy. Reason: Larval arrest is a well-replicated loss-of-function phenotype, and TOR-dependent growth signalling is needed for larval progression. It is a pleiotropic consequence of losing the central growth kinase rather than a specific developmental activity, so the row is kept as non-core. The cached Hara et al. 2002 entry is abstract-only; the abstract compares raptor RNAi phenotypes with Ce-TOR inactivation. The curator had the full text, so the row is not second-guessed. Supporting Evidence: PMID:12150926 RNAi of C. elegans raptor yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR PMID:23705068 LET-363/TOR, a key component of both TORC1 and TORC2, plays critical regulatory roles in a broad range of developmental stages
GO:0002119 nematode larval development	IMP PMID:12225660 TOR deficiency in C. elegans causes developmental arrest and...	KEEP AS NON CORE	Summary: let-363 loss of function (mutation or RNAi) causes larval arrest at mid-to-late L3, with gonadal degeneration and intestinal atrophy. Reason: Larval arrest is a well-replicated loss-of-function phenotype, and TOR-dependent growth signalling is needed for larval progression. It is a pleiotropic consequence of losing the central growth kinase rather than a specific developmental activity, so the row is kept as non-core. Supporting Evidence: PMID:12225660 TOR deficiency results in developmental arrest at mid-to-late L3 PMID:23705068 LET-363/TOR, a key component of both TORC1 and TORC2, plays critical regulatory roles in a broad range of developmental stages
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of protein serine/threonine kinase activity across the PIKK family (TOR, ATM, ATR, DNA-PK, SMG1). Reason: LET-363 has an intact PI3K/PI4K-type catalytic domain and the TOR catalytic signature (IPR026683). The IBA agrees with direct worm evidence: native TORC1 phosphorylates substrate peptides in vitro. The worm gene (WB:WBGene00002583) is among the IBD sources, which reflects its own experimental grounding. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy file:worm/let-363/let-363-uniprot.txt Belongs to the PI3/PI4-kinase family
GO:0004674 protein serine/threonine kinase activity	IDA PMID:35479415 The TORC1 phosphoproteome in C. elegans reveals roles in tra...	ACCEPT	Summary: TORC1 was immunoprecipitated from worm lysates through endogenous DAF-15::mCherry and phosphorylated four DAF-15-dependent phosphosite peptides (ALY-2, RSP-6, VAV-1, EPG-3) on Ser/Thr, compared with alanine-substituted controls. Reason: This is direct biochemical evidence of Ser/Thr kinase activity for the worm TOR complex. LET-363 was the most abundant DAF-15 partner and the only kinase detected in the preparation, so the activity can be attributed to LET-363. This is the core catalytic function. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy PMID:35479415 Importantly, no other kinases were identified in the IP preparations PMID:35479415 The most abundant of these interactors was LET-363/Tor
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation from the TOR catalytic domain (IPR026683) and EC 2.7.11.1. Reason: Agrees with the IDA and IBA rows for the same term; the TOR catalytic domain signature supports Ser/Thr protein kinase activity. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PAINT 'is_active_in nucleus' propagated across PIKK family members, most of which (ATM, ATR, DNA-PK) are nuclear DNA-damage kinases. Reason: Nuclear pools of TOR exist in yeast and mammals, and UniProt records a nuclear location for LET-363 from Long et al. 2002. That paper is abstract-only in the cache, so the localization data could not be checked. The IBD seed list is dominated by DNA-damage PIKKs whose activity is nuclear, and no worm study places LET-363 kinase activity in the nucleus. The TORC1 outputs characterized in the worm (translation, autophagy) are cytoplasmic. The nuclear claim is plausible, but it is not where the core activity has been shown to act. Supporting Evidence: file:worm/let-363/let-363-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular-location mapping (SL-0191 Nucleus), which UniProt attributes to Long et al. 2002. Reason: The UniProt location rests on PMID:12225660 (ECO:0000269). That paper is abstract-only in our cache, so the claim is not verifiable here but is curated. WormBase made an IDA cytoplasm annotation from the same paper. Kept as non-core and consistent with the IBA nucleus row. Supporting Evidence: file:worm/let-363/let-363-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: PAINT cytoplasm propagation from TOR orthologs, including the worm gene itself. Reason: TOR complexes act in the cytoplasm, where they phosphorylate translation and autophagy regulators. WormBase has a direct IDA cytoplasm row for LET-363. No worm data resolve a finer compartment such as the lysosomal surface, so cytoplasm is as precise as the evidence allows. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy
GO:0005737 cytoplasm	IDA PMID:12225660 TOR deficiency in C. elegans causes developmental arrest and...	ACCEPT	Summary: WormBase IDA from Long et al. 2002, which characterized CeTOR expression. Reason: The cached paper is abstract-only and the abstract does not describe the localization experiment. The curator read the full text, and cytoplasmic TOR agrees with the IBA row and with TOR biology, so the row is accepted. Supporting Evidence: PMID:12225660 Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast.
GO:0005737 cytoplasm	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning prediction of cytoplasm. Reason: ARBA is an unvetted prediction, but the claim is independently supported by the IDA and IBA rows for the same term. It is accepted for consistency. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy
GO:0006417 regulation of translation	IMP PMID:12225660 TOR deficiency in C. elegans causes developmental arrest and...	MODIFY	Summary: CeTOR deficiency phenotypes resemble those of inactivating eIF-4G and eIF-2. The authors conclude that TOR is a major upstream regulator of global mRNA translation. Reason: The direction is known: loss of TOR reduces translation, so TOR promotes it. The more specific term, positive regulation of translation, is already on the gene (IMP, PMID:18804378). The replacement records the evidenced sign. Proposed replacements: positive regulation of translation Supporting Evidence: PMID:12225660 Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast. PMID:18804378 Reduction of let-363 led to a 50% decrease in 35S incorporation
GO:0008340 determination of adult lifespan	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA prediction of determination of adult lifespan. Reason: The ARBA rule is not itself evidence, but several worm studies show that reducing let-363 extends adult lifespan. Lifespan is an organism-level output of reduced TOR growth signalling, so the row is kept as non-core, consistent with the experimental rows. Supporting Evidence: PMID:18804378 Reduction of let-363 and daf-15 together led to a statistically-significant increase in lifespan in 3/4 experiments
GO:0008340 determination of adult lifespan	IGI PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha...	KEEP AS NON CORE	Summary: TOR knockdown further extends the lifespan of ife-2 (eIF4E) mutants. Reason: Genetic interaction showing that let-363 influences lifespan. This is a downstream organismal phenotype, so it is non-core. The paper is abstract-only, but the abstract states the result. Supporting Evidence: PMID:17277769 Knockdown of target of rapamycin (TOR), a phosphatidylinositol kinase-related kinase that controls protein synthesis in response to nutrient cues, further increases the longevity of ife-2 mutants.
GO:0008340 determination of adult lifespan	IGI PMID:18804378 The Target of Rapamycin pathway antagonizes pha-4/FoxA to co...	KEEP AS NON CORE	Summary: Lifespan extension from let-363/daf-15 RNAi requires pha-4/FoxA. Reason: A clear experimental link to adult lifespan, mediated through pha-4. It is an organismal consequence of TOR signalling and is kept as non-core. Supporting Evidence: PMID:18804378 Reduction of let-363 and daf-15 together led to a statistically-significant increase in lifespan in 3/4 experiments PMID:18804378 This analysis revealed that pha-4 was required for CeTOR-induced lifespan extension
GO:0008340 determination of adult lifespan	IMP PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha...	KEEP AS NON CORE	Summary: Reduced TOR signalling increases longevity. Reason: Consistent with several independent reports that let-363 reduction extends lifespan. Non-core organismal phenotype. Supporting Evidence: PMID:17277769 Knockdown of target of rapamycin (TOR), a phosphatidylinositol kinase-related kinase that controls protein synthesis in response to nutrient cues, further increases the longevity of ife-2 mutants.
GO:0016242 negative regulation of macroautophagy	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of negative regulation of macroautophagy from TOR orthologs (human MTOR, fly Tor, fission yeast Tor2, mouse Mtor). Reason: TORC1 suppression of autophagy is conserved, and the worm gene follows it: let-363 RNAi raises the number of LGG-1::GFP autophagic puncta. The autophagy regulator EPG-3/VMP1 is a direct in vitro TORC1 substrate in C. elegans. LET-363 is the kinase that performs the inhibitory phosphorylation, so it participates in the regulation rather than merely being required for it. Supporting Evidence: PMID:18282106 we observed a significant increase in the number of autophagic vesicles in their L3 progeny PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy
GO:0016301 kinase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO mapping of the PI3/4-kinase conserved site (IPR018936) to kinase activity. Reason: Correct but uninformative. TOR is a PI3K-related protein kinase with no demonstrated lipid kinase activity; the evidence supports protein serine/threonine kinase activity, which the gene already carries by IDA and IBA. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy file:worm/let-363/let-363-uniprot.txt Serine/threonine-protein kinase that regulates the mRNA translation machinery, probably by modulating the activity of translation factors such as eIF-4G and eIF-2
GO:0031929 TOR signaling	IEA GO_REF:0000117	MODIFY	Summary: ARBA prediction of TOR signaling. Reason: LET-363 is the catalytic core of TOR signalling, but the term is general. The worm evidence separates its role in TORC1 signalling (with DAF-15) from its role in TORC2 signalling (with RICT-1), and both specific child terms are on the gene by IBA. Both are listed as replacements. Proposed replacements: TORC1 signaling TORC2 signaling Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15 PMID:23705068 this lipid function is mediated by TORC1 and antagonized by the NPRL-2/3 complex in the intestine PMID:23973804 inactivation of the TORC2 core components rict-1, let-363/TOR, lst-8, and sinh-1 rescued skn-1 embryonic lethality
GO:0031929 TOR signaling	IMP PMID:18804378 The Target of Rapamycin pathway antagonizes pha-4/FoxA to co...	MODIFY	Summary: Sheaffer et al. place ruvb-1 in the CeTOR pathway using let-363 and daf-15 RNAi, judged by snoRNP localization, protein synthesis and lifespan. Reason: The experiments inactivate let-363 together with daf-15/Raptor and read out TORC1 outputs (protein synthesis, nucleolar FIB-1). The specific term is TORC1 signaling, which the gene already carries by IBA. Proposed replacements: TORC1 signaling Supporting Evidence: PMID:18804378 Reduction of let-363 led to a 50% decrease in 35S incorporation PMID:18804378 Inactivation of let-363/TOR produced similar defects, with low levels of FIB-1, which were localized to the nucleoplasm and nucleolar periphery
GO:0031931 TORC1 complex	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of TORC1 complex membership from TOR orthologs, including the worm gene. Reason: Supported by worm co-immunoprecipitation: LET-363 associates with DAF-15/Raptor, and DAF-15 IP-MS recovers LET-363 as its main partner. Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15 PMID:35479415 The most abundant of these interactors was LET-363/Tor
GO:0031931 TORC1 complex	IEA GO_REF:0000117	ACCEPT	Summary: ARBA prediction of TORC1 complex. Reason: Unvetted prediction, but independently supported by IPI evidence for the same term. Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15
GO:0031931 TORC1 complex	IPI PMID:21952218 A shift of the TOR adaptor from Rictor towards Raptor by sem...	ACCEPT	Summary: Epitope-tagged LET-363 co-immunoprecipitates DAF-15/Raptor; DAF-15 IP contains LET-363 but not RICT-1. Reason: Direct physical evidence that LET-363 is the catalytic subunit of a DAF-15-containing TORC1 in C. elegans, confirmed with endogenous DAF-15 by IP-MS (PMID:35479415). Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15 PMID:35479415 The most abundant of these interactors was LET-363/Tor
GO:0031932 TORC2 complex	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of TORC2 complex membership. Reason: Supported by worm co-IP of LET-363 with RICT-1/Rictor, separate from DAF-15. Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15
GO:0031932 TORC2 complex	IPI PMID:21952218 A shift of the TOR adaptor from Rictor towards Raptor by sem...	ACCEPT	Summary: Epitope-tagged LET-363 co-immunoprecipitates RICT-1; RICT-1 IP contains LET-363 but not DAF-15. Reason: Direct physical evidence for a LET-363/RICT-1 TORC2 complex, whose assembly is regulated by semaphorin signalling. Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15 PMID:21952218 the SMP signal through PLX-1 serves to promote a shift of the LET-363-associated adaptor from RICT-1 towards DAF-15
GO:0038202 TORC1 signaling	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of TORC1 signaling. Reason: LET-363 is the kinase of worm TORC1. TORC1 phosphorylates substrates in vitro, mediates lipid (d17iso-GlcCer) and nutrient signals for postembryonic growth, and regulates translation and autophagy. This is a core process. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy PMID:23705068 this lipid function is mediated by TORC1 and antagonized by the NPRL-2/3 complex in the intestine PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15
GO:0038203 TORC2 signaling	IBA GO_REF:0000033	ACCEPT	Summary: PAINT propagation of TORC2 signaling. Reason: LET-363 forms TORC2 with RICT-1. Worm genetics place TORC2 (rict-1, lst-8, sinh-1, let-363) upstream of SGK-1 in embryonic and male-tail contexts. LET-363 is the catalytic subunit, so it does the kinase step of this signalling. Supporting Evidence: PMID:21952218 the LET-363 IP contained both DAF-15 and RICT-1 (Fig. 2b). On the other hand, the DAF-15 IP contained LET-363 but not RICT-1, whereas the RICT-1 IP contained LET-363 but not DAF-15 PMID:23973804 inactivation of the TORC2 core components rict-1, let-363/TOR, lst-8, and sinh-1 rescued skn-1 embryonic lethality
GO:0044877 protein-containing complex binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO mapping from the FRB domain (IPR009076/IPR036738) to protein-containing complex binding. Reason: The FRB domain binds the FKBP12-rapamycin complex, which is a drug-dependent interaction, and in mammals it also contacts some substrates. 'Protein-containing complex binding' captures neither a physiological activity nor TOR's role inside TORC1/TORC2, which the complex CC terms already record. No worm evidence shows LET-363 binding a pre-formed complex. The domain-to-term mapping is therefore an over-annotation. Supporting Evidence: file:worm/let-363/let-363-uniprot.txt FKBP12-rapamycin binding domain
GO:0045727 positive regulation of translation	IEA GO_REF:0000117	ACCEPT	Summary: ARBA prediction of positive regulation of translation. Reason: Unvetted prediction, but independently supported by worm experiments (35S incorporation, translation-factor phenocopies) and the IMP row for the same term. Supporting Evidence: PMID:18804378 Reduction of let-363 led to a 50% decrease in 35S incorporation PMID:12225660 Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast.
GO:0045727 positive regulation of translation	IMP PMID:18804378 The Target of Rapamycin pathway antagonizes pha-4/FoxA to co...	ACCEPT	Summary: let-363 RNAi in adults halves 35S-methionine incorporation into protein. Reason: Direct measurement that TOR promotes protein synthesis in vivo. This matches the conserved TORC1 role, in which the kinase phosphorylates translation regulators such as S6K and 4E-BP, and the worm phenocopies of eIF-4G and eIF-2 loss (PMID:12225660). Core TORC1 output. Supporting Evidence: PMID:18804378 Reduction of let-363 led to a 50% decrease in 35S incorporation PMID:12225660 Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast.
GO:0048382 mesendoderm development	IGI PMID:23973804 TORC2 signaling antagonizes SKN-1 to induce C. elegans mesen...	MARK AS OVER ANNOTATED	Summary: let-363 RNAi slightly suppresses skn-1 embryonic lethality (1.1% viable vs 0%). Ruf et al. attribute the effect to TORC2 (rict-1/sgk-1) antagonizing SKN-1-dependent mesendoderm specification. Reason: The let-363 interaction is weak, and the authors call it mild. It is a suppression in a sensitized skn-1 background: loss of TORC2 lets a few skn-1 embryos specify mesendoderm. That shows TORC2 opposing a developmental outcome under one genetic condition. It does not show LET-363 contributing to mesendoderm development in wild-type embryos, where let-363 RNAi does not prevent mesendoderm formation. The TORC2 signalling row covers the mechanistic role. Supporting Evidence: PMID:23973804 1.1% of eggs produced by skn-1(zu67);let-363(RNAi) gave rise to viable offspring compared to 0% of skn-1(zu67) PMID:23973804 genetic inhibition of the TOR kinase let-363 only had a mild effect on skn-1 associated lethality
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-based mapping (RHEA:17989, L-seryl-protein phosphorylation) to protein serine kinase activity. Reason: Consistent with the demonstrated Ser/Thr kinase activity. Three of the four TORC1 target sites identified in worms were serines. Supporting Evidence: PMID:35479415 Among the eighteen candidates tested, four peptides were identified as direct TORC1 targets by this strategy
GO:0160108 animal gross anatomical part developmental process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA prediction of animal gross anatomical part developmental process. Reason: This high-level grouping term comes from an unvetted machine-learning rule and names no specific structure. The developmental phenotypes of let-363 (larval arrest, germline progenitor depletion, ray morphogenesis defects) are pleiotropic consequences of losing growth signalling and are already covered by nematode larval development. The term adds no information. Supporting Evidence: PMID:12225660 TOR deficiency results in developmental arrest at mid-to-late L3

Gene Description

Existing Annotations Review

Core Functions

Catalytic subunit of TORC1 (with DAF-15/Raptor). Phosphorylates Ser/Thr residues on substrates and couples nutrient and lipid signals to growth: it promotes translation and ribosome biogenesis and restrains autophagy.

Catalytic subunit of TORC2 (with RICT-1/Rictor). It signals through SGK-1 in embryonic, male tail and metabolic contexts; semaphorin signalling regulates how much LET-363 is partitioned into TORC2 rather than TORC1.

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