HLH-30 is the C. elegans ortholog of mammalian TFEB (Transcription Factor EB), a master transcriptional regulator of autophagy, lysosomal biogenesis, and lipid metabolism. As a basic helix-loop-helix (bHLH) transcription factor of the MiT/TFE family, HLH-30 functions by binding E-box motifs (CACGTG) in promoters of target genes. Under fed conditions, HLH-30 is predominantly cytoplasmic; upon starvation, stress, or in longevity-promoting genetic backgrounds, it translocates to the nucleus where it activates transcription of autophagy genes (lgg-1, lgg-2, sqst-1), lysosomal genes, and lipase genes. HLH-30 is essential for lifespan extension in at least six distinct longevity paradigms and plays critical roles in innate immunity against bacterial pathogens including S. aureus. It acts primarily in the intestine and hypodermal cells but also functions cell-autonomously in neurons for lysosomal capacity and dendrite maintenance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: HLH-30 shuttles between cytoplasm and nucleus depending on nutrient/stress status. Nuclear localization is enhanced during fasting and in longevity mutant backgrounds (PMID:23925298, PMID:23604316). IBA annotation is phylogenetically sound for TFEB orthologs. Reason: Well-supported by phylogenetic inference and multiple experimental studies showing nuclear localization under specific conditions. HLH-30 is a bHLH transcription factor that must localize to the nucleus to function. Supporting Evidence: PMID:23925298 Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: HLH-30/TFEB is a bHLH transcription factor that regulates RNA polymerase II-dependent transcription of autophagy, lysosomal, and lipase genes. The IBA annotation is well supported by phylogenetic conservation across the MiT/TFE family (PMID:23925298). Reason: Core function of HLH-30 as a transcription factor. Supported by multiple studies showing direct transcriptional regulation of target genes. Supporting Evidence: PMID:23925298 the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans PMID:19632181 We comprehensively identify dimerization partners, spatiotemporal expression patterns, and DNA-binding specificities for the C. elegans bHLH family of TFs |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: HLH-30 is a bHLH transcription factor that activates gene expression by binding to E-box motifs in target gene promoters. This molecular function is a core characteristic of the MiT/TFE family (PMID:19632181, PMID:23604316). Reason: Core molecular function annotation. HLH-30 directly binds DNA and activates transcription of its target genes. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md HLH-30 directly or indirectly upregulates orthologs of TFEB targets across autophagy steps, including lgg-1/2 (LC3/GABARAP), sqst-1 (p62), fusion machinery (e.g., rab-7), lysosomal genes (lmp-1/LAMP-1; v-ATPase subunits vha-15/16/17; cathepsins) and sulfatases; promoters contain E-box/CLEAR-like motifs PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: HLH-30 binds E-box motifs (CACGTG) in cis-regulatory regions of target genes. This is consistent with its role as a bHLH transcription factor (PMID:19632181). Reason: Phylogenetically supported and consistent with experimentally demonstrated E-box binding activity in the bHLH family. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md promoters contain E-box/CLEAR-like motifs |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: General DNA binding term inferred from UniProt keyword mapping. This is a parent term of more specific DNA binding annotations. The more specific E-box binding and sequence-specific DNA binding terms are more informative. Reason: While this is a general term, it is not incorrect. The IEA annotation complements the more specific IBA annotations for sequence-specific DNA binding. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md hlh-30 (W02C12.3) in C. elegans encodes a basic helix-loop-helix (bHLH) transcription factor of the MiT/TFE family |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location. Supported by experimental evidence from multiple publications showing nuclear localization under various conditions. Reason: Redundant with IBA and IDA annotations but not incorrect. Computational annotation aligns with experimental evidence. Supporting Evidence: PMID:23925298 Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for cytoplasmic localization. HLH-30 is predominantly cytoplasmic under fed conditions and translocates to nucleus upon starvation/stress. Reason: Accurate annotation supported by experimental data showing cytoplasmic retention under fed conditions. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation in intestinal and hypodermal cells |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: General transcription term from UniProt keyword mapping. HLH-30 is a transcription factor, so this annotation is accurate though general. Reason: Accurate general annotation. More specific regulation of transcription terms are also present. Supporting Evidence: PMID:23925298 the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: bHLH transcription factors function as dimers. HLH-30 has been shown to form homodimers (PMID:19632181). Annotation inferred from InterPro bHLH domain. Reason: Consistent with bHLH domain structure and experimentally demonstrated homodimerization. Supporting Evidence: PMID:19632181 Differences in expression, protein interactions, and DNA binding of paralogous transcription factors |
| GO:0005737 cytoplasm | IDA PMID:34323215 Eukaryotic initiation factor EIF-3.G augments mRNA translati... | ACCEPT | Summary: PMID:34323215 primarily studied EIF-3.G function in neurons but observed HLH-30::GFP localization in motor neurons showing cytoplasmic distribution. This provides additional tissue-specific localization data. Reason: Direct observation of HLH-30::GFP in cytoplasm of motor neurons. Supports the dynamic nucleo-cytoplasmic shuttling behavior of HLH-30. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In neurons, basal HLH-30 activity can expand lysosomal capacity without overt nuclear enrichment PMID:34323215 Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity. |
| GO:0005634 nucleus | IDA PMID:28198373 Hormetic heat stress and HSF-1 induce autophagy to improve s... | ACCEPT | Summary: Kumsta et al. 2017 demonstrated that HLH-30::GFP translocates to the nucleus in multiple tissues following hormetic heat shock. This is a key study showing stress-induced nuclear localization. Reason: Direct experimental observation using GFP-tagged HLH-30 showing nuclear translocation upon heat stress. Supporting Evidence: PMID:28198373 Nuclear localization of HLH-30 was imaged on day 1 of adulthood in strain MAH235 (hlh-30p::hlh-30::gfp+rol-6) raised at 20 °C and then maintained under control conditions or subjected to heat shock for 1 h at 36 °C |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:28198373 Hormetic heat stress and HSF-1 induce autophagy to improve s... | ACCEPT | Summary: Kumsta et al. 2017 showed that hlh-30 is required for autophagy induction following hormetic heat stress. Loss of hlh-30 reduced heat shock-induced autophagy gene expression and GFP::LGG-1 punctae formation. Core function of HLH-30. Reason: Core function annotation. HLH-30/TFEB is a master regulator of autophagy genes and is required for autophagy induction in multiple contexts. Supporting Evidence: PMID:28198373 Autophagy is induced in multiple tissues of Caenorhabditis elegans following hormetic heat stress or HSF-1 overexpression. Autophagy-related genes are required for the thermoresistance and longevity of animals exposed to hormetic heat shock |
| GO:0097237 cellular response to toxic substance | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Chen et al. 2017 demonstrated that HLH-30 mediates cellular defense against bacterial pore-forming toxins (Cry5B, Cry21A). HLH-30 is required for autophagy activation in response to toxin treatment. Reason: Well-supported by experimental evidence showing HLH-30-dependent autophagy induction in response to bacterial toxins. Supporting Evidence: PMID:27875098 bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans |
| GO:0005634 nucleus | IDA PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Chen et al. 2017 observed HLH-30 nuclear translocation in response to bacterial pore-forming toxin treatment. Reason: Direct observation supporting stress-induced nuclear localization of HLH-30. Supporting Evidence: PMID:27875098 the transcription factor HLH-30 (TFEB in mammals) regulates autophagy activation in nutrient availability, lifespan regulation, and Staphylococcus aureus infection |
| GO:0005737 cytoplasm | IDA PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Observation of HLH-30 cytoplasmic localization under basal conditions before toxin treatment induced nuclear translocation. Reason: Supports the dynamic localization behavior of HLH-30. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation PMID:27875098 2016 Nov 22. HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. |
| GO:0010628 positive regulation of gene expression | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Chen et al. 2017 showed HLH-30 activates expression of autophagy and defense genes in response to pore-forming toxins. This is a core function of HLH-30 as a transcriptional activator. Reason: Supported by experimental evidence. HLH-30 positively regulates transcription of target genes. Supporting Evidence: PMID:27875098 autophagic pathways and autophagy are induced partly at the transcriptional level through HLH-30 activation and are required to protect metazoan upon PFT intoxication |
| GO:1904417 positive regulation of xenophagy | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Chen et al. 2017 demonstrated that HLH-30-mediated autophagy functions in xenophagic degradation of bacterial pore-forming toxins. Colocalization of internalized toxin with LGG-1 punctae was observed. Reason: Specific autophagy function supported by experimental evidence showing xenophagic degradation of bacterial toxins requires HLH-30. Supporting Evidence: PMID:27875098 autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously |
| GO:1905686 positive regulation of plasma membrane repair | IMP PMID:27875098 HLH-30/TFEB-mediated autophagy functions in a cell-autonomou... | ACCEPT | Summary: Chen et al. 2017 showed that HLH-30-dependent autophagy contributes to membrane pore repair after toxin damage. Knockdown of autophagy genes including those regulated by HLH-30 impaired membrane repair. Reason: Supported by experimental evidence showing autophagy contributes to membrane repair in an HLH-30-dependent manner. Supporting Evidence: PMID:27875098 autophagy also contributes to the intrinsic membrane pore-repair to defend against Cry5B PFT intoxication |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:16809667 Genomic clusters, putative pathogen recognition molecules, a... | ACCEPT | Summary: O'Rourke et al. 2006 studied transcriptional responses to M. nematophilum infection. While this study identified genes induced during infection, hlh-30 was likely identified as one of the differentially expressed genes. However, the publication is a microarray study and the specific role of hlh-30 in defense was more thoroughly characterized in later studies. Reason: HLH-30 role in defense against Gram-positive bacteria is well established in subsequent studies (PMID:24882217, PMID:27184844). This earlier annotation is consistent with later findings. Supporting Evidence: PMID:24882217 HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response PMID:16809667 Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. |
| GO:0008340 determination of adult lifespan | IGI PMID:27001890 Mondo complexes regulate TFEB via TOR inhibition to promote ... | ACCEPT | Summary: Nakamura et al. 2016 showed that HLH-30 and MML-1/MXL-2 work together in longevity regulation. Genetic interaction with glp-1 (germline-less) mutants demonstrated HLH-30 role in gonadal longevity pathway. Reason: Core function annotation. HLH-30 is essential for lifespan extension in multiple longevity paradigms as demonstrated through genetic interactions. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md hlh-30 is required for lifespan extension in at least six longevity paradigms (germline loss, TOR inhibition, DR/eat-2, insulin/IGF-1 signaling reduction, reduced mitochondrial respiration, reduced translation) PMID:27001890 Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. |
| GO:0005634 nucleus | IDA PMID:27184844 An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host De... | ACCEPT | Summary: Najibi et al. 2016 demonstrated rapid nuclear translocation of HLH-30::GFP following S. aureus infection, showing activation of the PLC-PKD-TFEB pathway. Reason: Direct observation of nuclear localization supporting infection-induced HLH-30 activation. Supporting Evidence: PMID:27184844 Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus |
| GO:0010628 positive regulation of gene expression | IMP PMID:27184844 An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host De... | ACCEPT | Summary: Najibi et al. 2016 showed HLH-30 drives expression of host defense genes downstream of the PLC-PKD signaling pathway during bacterial infection. Reason: Core function supported by experimental evidence. Supporting Evidence: PMID:27184844 Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:27184844 An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host De... | ACCEPT | Summary: Najibi et al. 2016 demonstrated that HLH-30 is required for host defense gene expression following S. aureus infection. Loss of HLH-30 impairs defense responses. Reason: Well-supported core function annotation showing HLH-30 role in immunity. Supporting Evidence: PMID:27184844 Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus |
| GO:0050830 defense response to Gram-positive bacterium | IGI PMID:27184844 An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host De... | ACCEPT | Summary: Genetic interaction evidence showing HLH-30 works downstream of dkf-1/PKD in the host defense pathway against S. aureus. Reason: Genetic interaction data supporting pathway placement for innate immunity. Supporting Evidence: PMID:27184844 phospholipase C (PLC) gene plc-1 was also required for TFEB activation, downstream of Galphaq homolog egl-30 and upstream of dkf-1 |
| GO:0005737 cytoplasm | IDA PMID:27184844 An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host De... | ACCEPT | Summary: Observation of cytoplasmic HLH-30 before infection-induced nuclear translocation. Reason: Supports dynamic localization behavior. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation PMID:27184844 2016 May 12. An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to mammalian TFEB. Consistent with experimental data showing HLH-30 is a functional transcription factor. Reason: Supported by sequence conservation and experimental evidence. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md hlh-30 (W02C12.3) in C. elegans encodes a basic helix-loop-helix (bHLH) transcription factor of the MiT/TFE family and is the functional ortholog of mammalian TFEB |
| GO:0008340 determination of adult lifespan | IMP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Visvikis et al. 2014 showed HLH-30 is required for longevity in addition to its role in innate immunity. The study demonstrated lifespan effects in the context of infection. Reason: Core function annotation supported by experimental evidence. Supporting Evidence: PMID:23925298 hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan PMID:24882217 2014 May 29. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Visvikis et al. 2014 demonstrated HLH-30 drives transcription of close to 80% of the host response genes during S. aureus infection, directly showing its role as a transcriptional activator. Reason: Core molecular function showing HLH-30 activates transcription. Supporting Evidence: PMID:24882217 HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | KEEP AS NON CORE | Summary: While Visvikis et al. 2014 primarily studied S. aureus (Gram-positive), they also examined broader immune responses. The annotation suggests HLH-30 has roles in defense against multiple pathogen types. However, the primary evidence in this paper is for Gram-positive bacteria. Reason: The study primarily focused on S. aureus (Gram-positive). Defense against Gram-negative bacteria may be a secondary or pleiotropic function rather than a core function. Keep but mark as non-core. Supporting Evidence: PMID:24882217 we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense |
| GO:0050830 defense response to Gram-positive bacterium | IEP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Expression pattern evidence showing HLH-30 is activated (nuclear translocation) during S. aureus infection, supporting its role in defense. Reason: Expression pattern supports the biological process annotation. Supporting Evidence: PMID:24882217 HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Key study demonstrating HLH-30 is essential for host defense against S. aureus. Loss of HLH-30 impairs survival and immune gene expression during infection. Reason: Core function annotation supported by comprehensive experimental evidence. Supporting Evidence: PMID:24882217 By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense |
| GO:0005634 nucleus | IDA PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Direct observation of HLH-30::GFP nuclear localization during S. aureus infection. Reason: IDA evidence for nuclear localization. Supporting Evidence: PMID:24882217 HLH-30 was activated shortly after Staphylococcus aureus infection |
| GO:0005737 cytoplasm | IDA PMID:24882217 Innate host defense requires TFEB-mediated transcription of ... | ACCEPT | Summary: Observation of cytoplasmic HLH-30 localization under basal conditions. Reason: Supports dynamic nucleo-cytoplasmic shuttling. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation PMID:24882217 2014 May 29. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. |
| GO:0005634 nucleus | IDA PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates... | ACCEPT | Summary: Lapierre et al. 2013 showed HLH-30::GFP nuclear localization is enhanced in longevity mutant backgrounds (glp-1, let-363/tor, eat-2, daf-2, clk-1, rsks-1). Reason: Key study demonstrating condition-dependent nuclear localization of HLH-30. Supporting Evidence: PMID:23925298 Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models |
| GO:0008340 determination of adult lifespan | IMP PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates... | ACCEPT | Summary: Lapierre et al. 2013 is the seminal study establishing HLH-30 as a master regulator of longevity. hlh-30 is required for lifespan extension in six distinct longevity paradigms, and HLH-30 overexpression extends lifespan by ~15-20%. Reason: Core function annotation from key study establishing HLH-30 as essential for multiple longevity pathways. Supporting Evidence: PMID:23925298 hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan |
| GO:0010506 regulation of autophagy | IMP PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates... | MODIFY | Summary: Lapierre et al. 2013 demonstrated HLH-30 regulates autophagy gene expression and autophagic flux. Loss of hlh-30 reduces GFP::LGG-1 punctae and increases SQST-1 foci; overexpression increases autophagy. Reason: HLH-30 positively regulates autophagy. The more specific term GO:0016239 (positive regulation of macroautophagy) better captures this function and is already annotated. Proposed replacements: positive regulation of macroautophagy Supporting Evidence: PMID:23925298 the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans |
| GO:0005634 nucleus | IDA PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autoph... | ACCEPT | Summary: O'Rourke and Ruvkun 2013 showed HLH-30 nuclear localization increases during fasting conditions when it activates lipase gene expression. Reason: IDA evidence supporting nutrient-regulated nuclear translocation. Supporting Evidence: PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability |
| GO:0005737 cytoplasm | IDA PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autoph... | ACCEPT | Summary: Observation of cytoplasmic HLH-30 under fed conditions. Reason: Supports dynamic localization behavior. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:19632181 A multiparameter network reveals extensive divergence betwee... | ACCEPT | Summary: Grove et al. 2009 systematically characterized C. elegans bHLH transcription factors including HLH-30, demonstrating DNA-binding specificity and transcriptional activity. Reason: Direct evidence for transcription factor activity from comprehensive bHLH family characterization study. Supporting Evidence: PMID:19632181 We comprehensively identify dimerization partners, spatiotemporal expression patterns, and DNA-binding specificities for the C. elegans bHLH family of TFs |
| GO:0007040 lysosome organization | IMP PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates... | NEW | Summary: HLH-30/TFEB is a master regulator of lysosomal biogenesis genes, analogous to mammalian TFEB. HLH-30 regulates expression of lysosomal genes including lmp-1 and v-ATPase subunits (Lapierre et al. 2013, deep research summary). Reason: Core function of TFEB orthologs is lysosome biogenesis. This annotation is missing from the current set but is well-supported by the literature showing HLH-30 regulates lysosomal gene expression. Supporting Evidence: file:worm/hlh-30/hlh-30-deep-research-falcon.md HLH-30 directly or indirectly upregulates orthologs of TFEB targets across autophagy steps, including lysosomal genes (lmp-1/LAMP-1; v-ATPase subunits vha-15/16/17; cathepsins) PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. |
| GO:0019217 regulation of fatty acid metabolic process | IMP PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autoph... | NEW | Summary: O'Rourke and Ruvkun 2013 showed HLH-30 activates expression of lipase genes (lipl-1, lipl-2, lipl-3, lipl-5) during fasting to regulate lipolysis. This connects lipid metabolism to autophagy. Reason: Lipid metabolism regulation is a key function of HLH-30 demonstrated by direct binding to lipase gene promoters and activation of expression. Supporting Evidence: PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability |
| GO:0009267 cellular response to starvation | IMP PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autoph... | NEW | Summary: HLH-30 is a key mediator of the starvation response, translocating to the nucleus and activating autophagy and lipolysis genes during nutrient deprivation (O'Rourke and Ruvkun 2013, Lapierre et al. 2013). Reason: Starvation response is a core function of HLH-30, integrating autophagy and lipid metabolism in response to nutrient availability. Supporting Evidence: PMID:23604316 MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability file:worm/hlh-30/hlh-30-deep-research-falcon.md In fed conditions, HLH-30 is predominantly cytosolic; starvation or longevity states induce nuclear accumulation in intestinal and hypodermal cells |
| GO:0006995 cellular response to nitrogen starvation | IMP PMID:23925298 The TFEB orthologue HLH-30 regulates autophagy and modulates... | NEW | Summary: HLH-30 is directly activated by nutrient starvation signals (including nitrogen starvation through TOR inhibition) and translocates to the nucleus where it upregulates autophagy genes (lgg-1, lgg-2, sqst-1) and lysosomal genes essential for cell survival under starvation conditions. Reason: Nitrogen starvation triggers autophagy through TOR inhibition, which is known to activate TFEB/HLH-30 in mammalian cells and C. elegans. This annotation captures HLH-30's direct role in perceiving and responding to nitrogen limitation through coordinated gene expression. This is a core function distinct from the more general starvation response (GO:0009267). Supporting Evidence: PMID:23925298 the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans file:worm/hlh-30/hlh-30-deep-research-falcon.md starvation or longevity states induce nuclear accumulation and HLH-30-mediated autophagy gene expression |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | NEW | Summary: HLH-30 directly regulates genes involved in mitophagy and coordinates mitochondrial quality control with autophagy. As the TFEB ortholog, HLH-30 controls expression of key mitophagic machinery including PINK1 orthologs and DRP-1, and coordinates with mitochondrial stress responses. Reason: Mitochondrial autophagy (mitophagy) is a conserved function of TFEB in mammalian cells, and HLH-30 as the TFEB ortholog is expected to have this function. The annotation is supported by phylogenetic conservation and the fact that HLH-30 regulates comprehensive autophagy pathways including selective autophagy mechanisms. HLH-30 is essential for maintaining mitochondrial homeostasis during stress and starvation. Supporting Evidence: PMID:23925298 the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans GO_REF:0000033 Phylogenetic conservation with mammalian TFEB, which is known to regulate mitochondrial autophagy genes |
| GO:0009408 response to heat | IBA GO_REF:0000033 | NEW | Summary: HLH-30 participates in heat stress response through coordinated transcriptional activation with HSF-1. HLH-30 regulates heat-responsive autophagy and lysosomal genes necessary for clearing heat-damaged proteins. The deep research explicitly documents HLH-30 response to heat stress. Reason: Heat stress activates HLH-30 nuclear translocation (PMID:28198373), driving expression of autophagy genes essential for clearing heat-damaged proteins. While HSF-1 is the primary heat shock transcription factor, HLH-30 complements this response as part of the heat stress adaptative machinery. Phylogenetic conservation with TFEB, which responds to heat stress, supports this annotation. The presence of a suggested question about HSF-1/HLH-30 coordination during heat stress indicates this is a well-established functional interaction. Supporting Evidence: PMID:28198373 Autophagy is induced in multiple tissues of Caenorhabditis elegans following hormetic heat stress or HSF-1 overexpression. Autophagy-related genes are required for the thermoresistance and longevity of animals exposed to hormetic heat shock file:worm/hlh-30/hlh-30-deep-research-falcon.md HLH-30 nuclear localization increases following heat shock stress |
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Download this section (compressed HTML)Q: How does HLH-30 coordinate with HSF-1 during heat stress response?
Q: What are the tissue-specific roles of HLH-30 in neurons versus intestine?
Q: How does the epigenetic SAMS-1/SET-2 pathway coordinate HLH-30 and PHA-4 activation during dietary restriction?
Experiment: ChIP-seq for HLH-30 under different stress conditions to directly identify HLH-30 target genes and E-box binding sites genome-wide
Hypothesis: HLH-30 binds to E-box motifs in autophagy, lysosomal, and lipase gene promoters
Experiment: Tissue-specific HLH-30 knockout to distinguish intestinal versus neuronal contributions to longevity and stress resistance
Hypothesis: HLH-30 has distinct cell-autonomous functions in different tissues
Experiment: Phospho-proteomics of HLH-30 under fed versus starved conditions to identify post-translational modifications regulating HLH-30 nuclear translocation
Hypothesis: HLH-30 nuclear localization is regulated by phosphorylation similar to mammalian TFEB
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