Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004672 protein kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: NSY-1 possesses protein kinase activity as demonstrated by direct biochemical assays. The IBA annotation is supported by phylogenetic inference across multiple orthologs including mammalian ASK1. Reason: This is a core molecular function of NSY-1. The protein kinase activity is well-established through biochemical studies (PMID:11336672, PMID:11751572). The IBA annotation from phylogenetic analysis is consistent with experimental evidence. Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase kinase (MAPKKK), respectively PMID:11336672 nsy-1 encodes a homolog of the human MAP kinase kinase kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases file:worm/nsy-1/nsy-1-deep-research-falcon.md model: Edison Scientific Literature
GO:0007254 JNK cascade	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: The IBA annotation indicates NSY-1 involvement in the JNK cascade based on phylogenetic inference. While there is some evidence for JNK pathway involvement in C. elegans stress responses involving nsy-1, the primary established role is in the p38 MAPK cascade. Reason: The mammalian ortholog ASK1 activates both p38 and JNK pathways. In C. elegans, there is evidence for JNK involvement in stress responses (PMID:15256590 shows JNK pathways defend against bacterial toxins), but the core established function of nsy-1 is in the p38 cascade via sek-1/pmk-1. The JNK cascade annotation is not wrong but represents a secondary function. Supporting Evidence: PMID:11336672 nsy-1 encodes a homolog of the human MAP kinase kinase kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases
GO:0038066 p38MAPK cascade	IBA GO_REF:0000033	ACCEPT	Summary: NSY-1 is a core component of the p38 MAPK cascade in C. elegans, acting as the MAP3K that phosphorylates SEK-1 (MAPKK), which then activates PMK-1 (p38 MAPK). This is strongly supported by IBA phylogenetic inference and extensive experimental evidence. Reason: This is a core function of NSY-1. The nsy-1/sek-1/pmk-1 p38 MAPK cascade is one of the best-characterized signaling pathways in C. elegans innate immunity and neuronal development (PMID:12142542, PMID:11751572). Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance: sek-1, which encodes a mitogen-activated protein (MAP) kinase kinase, and nsy-1, which encodes a MAP kinase kinase kinase
GO:0000165 MAPK cascade	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation based on InterPro domain mapping. NSY-1 contains a MAP3K domain and functions in the MAPK cascade. This is a parent term of the more specific p38MAPK cascade annotation. Reason: This broader term is correctly applied based on domain annotation. NSY-1 is indeed a MAP3K functioning in MAPK signaling. While more specific terms exist (p38MAPK cascade), this IEA annotation is not incorrect. Supporting Evidence: PMID:12142542 nsy-1, which encodes a MAP kinase kinase kinase
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: IEA annotation based on UniProt keyword mapping. As a kinase, NSY-1 binds ATP for its catalytic activity. This is a very general term. Reason: While technically correct (kinases bind nucleotides), this term is too general to be informative. The more specific term "ATP binding" (GO:0005524) is also annotated and is more appropriate for a kinase.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation based on InterPro domain mapping for protein kinase domain. This duplicates the IBA annotation with the same term but different evidence. Reason: Duplicate of IBA annotation - both are valid. The IEA provides independent support from domain analysis. Protein kinase activity is a core molecular function of NSY-1.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. NSY-1 is a serine/threonine kinase that phosphorylates SEK-1 on serine/threonine residues. Reason: This is an accurate more specific molecular function term. NSY-1 (ASK1 ortholog) is characterized as a serine/threonine kinase. The UniProt entry lists EC 2.7.11.25 (MAP kinase kinase kinase activity) which is a serine/threonine kinase. Supporting Evidence: UniProt:Q21029 Serine/threonine-protein kinase
GO:0004709 MAP kinase kinase kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation based on EC number and automated reasoning. NSY-1 has MAP3K activity, phosphorylating SEK-1 (MAPKK). Reason: This is the most specific and accurate molecular function term for NSY-1. It is also supported by direct experimental evidence (IDA from PMID:11751572). This IEA provides additional computational support. Supporting Evidence: UniProt:Q21029 Mitogen-activated protein kinase kinase kinase nsy-1
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation based on InterPro domain and UniProt keyword mapping. As a protein kinase, NSY-1 requires ATP binding for catalytic activity. Reason: ATP binding is essential for kinase activity. The protein contains a canonical ATP-binding site in its kinase domain. This is an appropriate molecular function annotation.
GO:0007399 nervous system development	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword "Neurogenesis". NSY-1 is involved in neuronal asymmetry determination during development. Reason: NSY-1 plays a well-established role in nervous system development, specifically in determining asymmetric odorant receptor expression in AWC neurons. This was the original context of nsy-1 discovery ("neuronal symmetry"). The term is appropriately broad. Supporting Evidence: PMID:11751572 the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development
GO:0016301 kinase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Very general term from UniProt keyword mapping. NSY-1 has kinase activity, but more specific terms are available and annotated. Reason: This is technically correct but overly general. More specific terms (protein kinase activity, MAP kinase kinase kinase activity) are already annotated and provide more useful information. This general term adds no value.
GO:0016740 transferase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Very general term from UniProt keyword mapping. Kinases are transferases, but this is at the root of the enzyme hierarchy. Reason: This is too general to be informative. While kinases are indeed transferases, this annotation provides no functional insight. More specific terms are already annotated.
GO:0030424 axon	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location vocabulary. NSY-1 localizes to axons in AWC neurons. Reason: NSY-1 localization to axons is experimentally demonstrated (PMID:15625192). The IEA annotation is consistent with experimental evidence. Supporting Evidence: PMID:15625192 TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression
GO:0043204 perikaryon	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location vocabulary. NSY-1 localizes to the neuronal cell body (perikaryon). Reason: NSY-1 localization to the perikaryon is supported by UniProt annotation based on experimental evidence (PMID:15625192).
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. NSY-1 requires Mg2+ as a cofactor for kinase activity. Reason: Kinases typically require divalent metal ions (Mg2+) as cofactors. The UniProt entry notes Mg2+ as a cofactor with experimental evidence (PMID:11751572).
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: IEA annotation from Rhea reaction mapping. NSY-1 phosphorylates serine residues on substrate proteins. Reason: NSY-1 catalyzes serine phosphorylation as part of its MAP3K activity. This is consistent with the catalytic activity annotations in UniProt (EC 2.7.11.25).
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to ba...	ACCEPT	Summary: IMP annotation showing nsy-1 positively regulates transcription of pgp-5 and other immune response genes. The p38 MAPK cascade activates transcription factors that drive gene expression. Reason: The nsy-1/sek-1/pmk-1 pathway regulates transcription of numerous genes including antimicrobial peptides and stress response genes. This is achieved through downstream transcription factors (PMID:17888400, PMID:17526726). Supporting Evidence: PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade.
GO:0050829 defense response to Gram-negative bacterium	IMP PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to ba...	ACCEPT	Summary: IMP annotation demonstrating nsy-1 is required for defense against Gram-negative bacteria including P. aeruginosa. Reason: This is a core biological process for nsy-1. The original identification of nsy-1 in innate immunity came from a screen for susceptibility to P. aeruginosa (Gram-negative) (PMID:12142542). Multiple studies confirm this role. Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance PMID:17888400 Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade.
GO:0004712 protein serine/threonine/tyrosine kinase activity	IDA PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	MODIFY	Summary: IDA annotation based on direct assay of NSY-1 kinase activity in PMID:11751572. The study demonstrated NSY-1 phosphorylates SEK-1. Reason: While NSY-1 has protein kinase activity demonstrated by direct assay, it is specifically a serine/threonine kinase (EC 2.7.11.25), not a dual-specificity kinase. The term "protein serine/threonine/tyrosine kinase activity" implies tyrosine kinase activity which is not demonstrated. A more accurate term would be "MAP kinase kinase kinase activity" (GO:0004709) which is already annotated with IDA from the same reference. Proposed replacements: MAP kinase kinase kinase activity Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase kinase (MAPKKK), respectively
GO:0006979 response to oxidative stress	IMP PMID:22308034 Stabilization of RNT-1 protein, runt-related transcription f...	ACCEPT	Summary: IMP annotation showing nsy-1 is required for the response to oxidative stress, specifically for stabilization of RNT-1 (RUNX transcription factor) during oxidative stress. Reason: NSY-1 plays a role in oxidative stress response through the p38 MAPK pathway. The study shows the MAP kinase pathway (including nsy-1) is required for RNT-1 stabilization in response to oxidative stress (PMID:22308034). Supporting Evidence: UniProt:Q21029 Plays a role in resistance to several environmental stresses including oxidative, protein misfolding (ER) and osmotic stresses PMID:22308034 Epub 2012 Feb 3. Stabilization of RNT-1 protein, runt-related transcription factor (RUNX) protein homolog of Caenorhabditis elegans, by oxidative stress through mitogen-activated protein kinase pathway.
GO:0140367 antibacterial innate immune response	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	ACCEPT	Summary: IMP annotation based on the landmark study identifying nsy-1 as required for resistance to bacterial pathogens. Reason: This is a core function of nsy-1. The study (PMID:12142542) demonstrated that nsy-1 mutants are hypersusceptible to bacterial pathogens including P. aeruginosa and E. faecalis, establishing the p38 MAPK pathway in C. elegans innate immunity. Supporting Evidence: PMID:12142542 These data suggest that this MAP kinase signaling cassette represents an ancient feature of innate immune responses in evolutionarily diverse species
GO:0010628 positive regulation of gene expression	IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia...	ACCEPT	Summary: IMP annotation showing nsy-1 positively regulates expression of antimicrobial peptide genes in response to fungal infection. Reason: NSY-1 is part of the p38 MAPK cascade that positively regulates antimicrobial peptide gene expression. The study shows nsy-1 is required for nlp-29 induction after D. coniospora infection (PMID:22470487). Supporting Evidence: PMID:22470487 We have shown that for nlp-29 cluster genes, following both infection and injury, inductive signaling passes via TPA-1, a protein kinase C delta (PKC∂) that acts upstream of TIR-1, the nematode ortholog of SARM, and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1, and PMK-1 [20]
GO:0050832 defense response to fungus	IMP PMID:22470487 The pseudokinase NIPI-4 is a novel regulator of antimicrobia...	ACCEPT	Summary: IMP annotation demonstrating nsy-1 is required for defense against the fungal pathogen Drechmeria coniospora. Reason: NSY-1 is required for the innate immune response to fungal infection. The study identified nsy-1 mutants as unable to induce antimicrobial peptide expression after D. coniospora infection (PMID:22470487). Supporting Evidence: PMID:22470487 We undertook a large-scale genetic screen for mutants that prevented the normal induction of a Pnlp-29::GFP reporter transgene after infection with D. coniospora
GO:0004709 MAP kinase kinase kinase activity	IDA PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	ACCEPT	Summary: IDA annotation based on direct biochemical demonstration that NSY-1 has MAP3K activity, phosphorylating SEK-1 (MAPKK). Reason: This is the most specific and accurate molecular function annotation for NSY-1. The study directly demonstrated NSY-1 kinase activity and its role as a MAP3K upstream of SEK-1 (PMID:11751572). Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase kinase (MAPKKK), respectively
GO:0005737 cytoplasm	IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies...	ACCEPT	Summary: IDA annotation showing NSY-1 localizes to the cytoplasm, based on fluorescence microscopy studies. Reason: NSY-1 localization to the cytoplasm is demonstrated in the Chuang & Bargmann study using NSY-1::GFP fusion proteins (PMID:15625192). Supporting Evidence: PMID:15625192 TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression
GO:0010628 positive regulation of gene expression	IMP PMID:17526726 Specificity and complexity of the Caenorhabditis elegans inn...	ACCEPT	Summary: IMP annotation showing nsy-1 positively regulates antimicrobial gene expression in response to bacterial pathogens. Reason: This is a core function of the nsy-1/p38 pathway. The study demonstrates differential regulation of antimicrobial genes by the p38 pathway including nsy-1 (PMID:17526726). Supporting Evidence: PMID:17526726 May 25. Specificity and complexity of the Caenorhabditis elegans innate immune response.
GO:1904115 axon cytoplasm	IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies...	ACCEPT	Summary: IDA annotation showing NSY-1 localizes to the axon cytoplasm, specifically in post-synaptic punctate structures in AWC neurons. Reason: The study directly visualized NSY-1::GFP localization to punctate structures in AWC axons (PMID:15625192). This is a more specific term than "axon" and appropriately captures the localization data. Supporting Evidence: PMID:15625192 TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression
GO:0018991 egg-laying behavior	IMP PMID:10571181 Lateral signaling mediated by axon contact and calcium entry...	KEEP AS NON CORE	Summary: IMP annotation indicating nsy-1 affects egg-laying behavior based on mutant phenotypes. Reason: While nsy-1 mutants do show egg-laying defects, this is likely a pleiotropic effect of disrupted p38 MAPK signaling rather than a direct role in egg-laying behavior. The primary paper (PMID:10571181) focuses on neuronal asymmetry. The annotation is valid but represents a secondary phenotype. Supporting Evidence: UniProt:Q21029 Involved in egg laying PMID:10571181 Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C.
GO:0008340 determination of adult lifespan	IMP PMID:23352664 A fasting-responsive signaling pathway that extends life spa...	KEEP AS NON CORE	Summary: IMP annotation based on the finding that nsy-1 is involved in fasting-responsive signaling that affects lifespan. Reason: The study (PMID:23352664) focuses on JNK (KGB-1) and AP-1 rather than nsy-1 as the primary mediators of fasting-induced longevity. NSY-1 may have a role through the broader MAPK signaling network, but this is not a core function. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C.
GO:0008340 determination of adult lifespan	IGI PMID:23352664 A fasting-responsive signaling pathway that extends life spa...	KEEP AS NON CORE	Summary: IGI annotation indicating genetic interaction affecting lifespan. Reason: As with the IMP annotation above, lifespan determination is not a core function of nsy-1. The genetic interaction evidence supports involvement but the primary pathway for fasting-induced longevity involves JNK/KGB-1 rather than the p38 pathway. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C.
GO:0042594 response to starvation	IMP PMID:23352664 A fasting-responsive signaling pathway that extends life spa...	KEEP AS NON CORE	Summary: IMP annotation indicating nsy-1 is involved in the response to starvation/fasting. Reason: While MAPK pathways are involved in stress responses including starvation, the study primarily implicates the JNK pathway (KGB-1) rather than the p38 pathway (nsy-1/sek-1/pmk-1) in fasting responses. This is not a core function. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C.
GO:0042594 response to starvation	IGI PMID:23352664 A fasting-responsive signaling pathway that extends life spa...	KEEP AS NON CORE	Summary: IGI annotation for genetic interaction in starvation response. Reason: Same reasoning as IMP annotation above - not a core function of nsy-1. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C.
GO:0093002 response to nematicide	TAS PMID:15256590 Mitogen-activated protein kinase pathways defend against bac...	ACCEPT	Summary: TAS annotation indicating nsy-1 is involved in defense against bacterial pore-forming toxins, which can act as nematicides. Reason: The study (PMID:15256590) demonstrates that p38 MAPK pathways including nsy-1 defend against the pore-forming toxin Cry5B from Bacillus thuringiensis, a natural nematicide. This is a valid biological process annotation. Supporting Evidence: PMID:15256590 A p38 mitogen-activated protein kinase (MAPK) kinase and a c-Jun N-terminal-like MAPK are both transcriptionally up-regulated by Cry5B
GO:0000165 MAPK cascade	IGI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	ACCEPT	Summary: IGI annotation based on genetic interaction with sek-1 (WBGene00004758) in the MAPK cascade for neuronal asymmetry. Reason: NSY-1 functions in the MAPK cascade upstream of SEK-1. The genetic interaction evidence demonstrates the pathway relationship (PMID:11751572). Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1
GO:0031434 mitogen-activated protein kinase kinase binding	IPI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	ACCEPT	Summary: IPI annotation based on physical interaction between NSY-1 and SEK-1 (MAPKK). Reason: NSY-1 physically interacts with SEK-1 as part of the MAPK signaling complex. This interaction is required for signal transduction (PMID:11751572). Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1 UniProt:Q21029 Interacts with sek-1
GO:0035545 determination of left/right asymmetry in nervous system	IMP PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	ACCEPT	Summary: IMP annotation based on the finding that nsy-1 mutants disrupt left/right asymmetric odorant receptor expression in AWC neurons. Reason: This is a core biological function of nsy-1 and the origin of its name ("neuronal symmetry"). The gene was identified in screens for mutants with symmetric str-2 expression in both AWC neurons (PMID:11751572). Supporting Evidence: PMID:11751572 the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development PMID:11336672 nsy-1 mutants express str-2 in both neurons, disrupting AWC asymmetry
GO:0035545 determination of left/right asymmetry in nervous system	IGI PMID:11751572 SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal as...	ACCEPT	Summary: IGI annotation based on genetic interaction with sek-1 in determination of neuronal asymmetry. Reason: The genetic interaction between nsy-1 and sek-1 in the asymmetry pathway is well-established (PMID:11751572). Supporting Evidence: PMID:11751572 Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1
GO:0050830 defense response to Gram-positive bacterium	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	ACCEPT	Summary: IMP annotation showing nsy-1 is required for defense against Gram-positive bacteria (E. faecalis tested). Reason: This is a core function of nsy-1. The landmark study (PMID:12142542) demonstrated nsy-1 mutants are susceptible to both Gram-positive (E. faecalis) and Gram-negative (P. aeruginosa) pathogens. Supporting Evidence: UniProt:Q21029 Involved in resistance to pathogenic Gram-positive and Gram-negative bacterial and fungal infection PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity.
GO:0050829 defense response to Gram-negative bacterium	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	ACCEPT	Summary: IMP annotation showing nsy-1 is required for defense against Gram-negative bacteria (P. aeruginosa). Reason: Core function - nsy-1 was identified in a screen for susceptibility to P. aeruginosa (PMID:12142542). This duplicates another annotation with the same term from PMID:17888400. Supporting Evidence: PMID:12142542 A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance
GO:0038066 p38MAPK cascade	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	ACCEPT	Summary: IMP annotation demonstrating nsy-1 functions in the p38 MAPK cascade for innate immunity. Reason: Core function - the study established that nsy-1/sek-1/pmk-1 constitute a conserved p38 MAPK cascade for innate immunity (PMID:12142542). Supporting Evidence: PMID:12142542 RNA interference assays and biochemical analysis established that a p38 ortholog, pmk-1, functions as the downstream MAP kinase required for pathogen defense
GO:1901046 positive regulation of egg-laying behavior	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	KEEP AS NON CORE	Summary: IMP annotation indicating nsy-1 positively regulates egg-laying behavior. Reason: While nsy-1 mutants show egg-laying defects, this is likely a secondary phenotype of disrupted MAPK signaling rather than a primary function. The reference (PMID:12142542) focuses on innate immunity, not egg-laying. Supporting Evidence: UniProt:Q21029 Involved in egg laying PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity.
GO:0014069 postsynaptic density	IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies...	ACCEPT	Summary: IDA annotation showing NSY-1 localizes to postsynaptic density in AWC neurons. Reason: NSY-1 localizes to postsynaptic regions where it co-localizes with TIR-1 (PMID:15625192). This localization is important for its role in neuronal asymmetry signaling. Supporting Evidence: PMID:15625192 TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression
GO:0043025 neuronal cell body	IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies...	ACCEPT	Summary: IDA annotation showing NSY-1 localizes to neuronal cell bodies (perikaryon). Reason: NSY-1::GFP localization studies showed expression in neuronal cell bodies in addition to axons (PMID:15625192). Supporting Evidence: PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling.
GO:0006935 chemotaxis	IMP PMID:11287957 C. elegans odour discrimination requires asymmetric diversit...	ACCEPT	Summary: IMP annotation showing nsy-1 affects chemotaxis behavior, specifically odor discrimination. Reason: nsy-1 mutants show defects in odor discrimination and chemotaxis due to disrupted AWC asymmetry. The study shows "nsy-1 mutants exhibit discrimination and olfactory defects" (PMID:11287957). Supporting Evidence: PMID:11287957 C. elegans odour discrimination requires asymmetric diversity in olfactory neurons.
GO:0045087 innate immune response	IMP PMID:12142542 A conserved p38 MAP kinase pathway in Caenorhabditis elegans...	ACCEPT	Summary: IMP annotation showing nsy-1 is required for innate immune response. Reason: This is a core function of nsy-1. The gene was identified in a screen for innate immunity mutants and is required for defense against pathogens (PMID:12142542). Supporting Evidence: PMID:12142542 These data suggest that this MAP kinase signaling cassette represents an ancient feature of innate immune responses in evolutionarily diverse species
GO:0045165 cell fate commitment	IMP PMID:10571181 Lateral signaling mediated by axon contact and calcium entry...	ACCEPT	Summary: IMP annotation indicating nsy-1 is involved in cell fate commitment, specifically in AWC neuronal asymmetry. Reason: NSY-1 is required for the commitment of AWC neurons to asymmetric fates (AWC-ON vs AWC-OFF). The pathway determines which neuron expresses str-2 (PMID:10571181, PMID:11751572). Supporting Evidence: PMID:11751572 the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development PMID:10571181 Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C.

Core Functions

NSY-1 is a MAP3K (MAP kinase kinase kinase) that phosphorylates and activates SEK-1 (MAPKK), which in turn activates PMK-1 (p38 MAPK). This is the core molecular function, with EC 2.7.11.25.

Molecular Function:

MAP kinase kinase kinase activity

Directly Involved In:

p38MAPK cascade

NSY-1 functions at the apex of the conserved p38 MAPK cascade (NSY-1/SEK-1/PMK-1) that determines left/right asymmetric odorant receptor (str-2) expression in AWC neurons. Acts downstream of TIR-1 and UNC-43/CaMKII.

Molecular Function:

MAP kinase kinase kinase activity

Directly Involved In:

determination of left/right asymmetry in nervous system

Cellular Locations:

postsynaptic density

NSY-1 is essential for defense against bacterial pathogens including both Gram-positive (E. faecalis) and Gram-negative (P. aeruginosa) bacteria through the p38 MAPK pathway.

Molecular Function:

MAP kinase kinase kinase activity

Directly Involved In:

antibacterial innate immune response defense response to Gram-negative bacterium defense response to Gram-positive bacterium

NSY-1 is required for the innate immune response to fungal pathogens such as Drechmeria coniospora, regulating antimicrobial peptide gene expression.

Molecular Function:

MAP kinase kinase kinase activity

Directly Involved In:

defense response to fungus

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10571181

Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C. elegans.

NSY-1 functions downstream of Ca2+ signaling and CaMKII (UNC-43) in AWC asymmetry

"CaMKII activity acts as a switch in the initial decision to express str-2; thus, calcium signals can define distinct cell types during neuronal development"
Calcium signals define distinct cell types during neuronal development

"calcium signals can define distinct cell types during neuronal development"

PMID:11287957

C. elegans odour discrimination requires asymmetric diversity in olfactory neurons.

nsy-1 mutants (including ky542) have STR-2 expressed in both AWC neurons

"ky542 is an allele of nsy-1, a neuronal symmetry, or Nsy, mutant in which STR-2 is expressed in both AWC neurons"
Nsy mutants exhibit chemotaxis and odor discrimination defects

"Other Nsy mutants exhibit discrimination and olfactory defects like those of nsy-1 mutants"

PMID:11336672

The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral signaling decision required for asymmetric olfactory neuron fates.

NSY-1 kinase activity demonstrated biochemically

"nsy-1 encodes a homolog of the human MAP kinase kinase kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases"
UNC-43/CaMKII activates NSY-1

"Based on genetic epistasis analysis, nsy-1 appears to act downstream of the CaMKII unc-43, and NSY-1 associates with UNC-43, suggesting that UNC-43/CaMKII activates the NSY-1 MAP kinase cassette"

PMID:11751572

SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric development in Caenorhabditis elegans.

NSY-1 is a MAP3K that phosphorylates SEK-1

"Genetic and biochemical analyses reveal that SEK-1 functions in a pathway downstream of UNC-43 and NSY-1, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase kinase (MAPKKK), respectively"
NSY-1/SEK-1/MAPK cascade activated by Ca2+ signaling

"the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development"
Pathway establishes asymmetric cell fate in AWC neurons

"the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ signaling through CaMKII and establishes asymmetric cell fate decision during neuronal development"

PMID:12142542

A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity.

nsy-1 mutants are susceptible to P. aeruginosa and E. faecalis

"A genetic screen for Caenorhabditis elegans mutants with enhanced susceptibility to killing by Pseudomonas aeruginosa led to the identification of two genes required for pathogen resistance"
NSY-1/SEK-1/PMK-1 constitute conserved p38 MAPK pathway for innate immunity

"RNA interference assays and biochemical analysis established that a p38 ortholog, pmk-1, functions as the downstream MAP kinase required for pathogen defense"
Ancient feature of innate immune responses

"These data suggest that this MAP kinase signaling cassette represents an ancient feature of innate immune responses in evolutionarily diverse species"

PMID:15256590

Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins.

p38 MAPK pathway defends against Cry5B pore-forming toxin

"A p38 mitogen-activated protein kinase (MAPK) kinase and a c-Jun N-terminal-like MAPK are both transcriptionally up-regulated by Cry5B"
MAPK pathways are functionally important for toxin defense

"Moreover, both MAPK pathways are functionally important because elimination of either leads to animals that are (i) hypersensitive to a low, chronic dose of toxin and (ii) hypersensitive to a high, brief dose of toxin such that the animal might naturally encounter in the wild"

PMID:15625192

A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling.

TIR-1 localizes NSY-1 to postsynaptic regions

"TIR-1 localizes NSY-1 to post-synaptic regions of AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression"
TIR-1 acts upstream of NSY-1 in asymmetry pathway

"Genetic evidence suggests that tir-1 acts downstream of a voltage-gated calcium channel and CaMKII (UNC-43) to regulate AWC asymmetry via the NSY-1(ASK1) p38/JNK MAP (mitogen-activated protein) kinase cascade"

PMID:17526726

Specificity and complexity of the Caenorhabditis elegans innate immune response.

PMID:17888400

Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade.

PMID:22308034

Stabilization of RNT-1 protein, runt-related transcription factor (RUNX) protein homolog of Caenorhabditis elegans, by oxidative stress through mitogen-activated protein kinase pathway.

PMID:22470487

The pseudokinase NIPI-4 is a novel regulator of antimicrobial peptide gene expression.

NSY-1 is part of MAPK cassette for antimicrobial peptide induction

"We have shown that for nlp-29 cluster genes, following both infection and injury, inductive signaling passes via TPA-1, a protein kinase C delta (PKC∂) that acts upstream of TIR-1, the nematode ortholog of SARM, and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1, and PMK-1 [20]"
Required for nlp-29 induction after D. coniospora infection

"We undertook a large-scale genetic screen for mutants that prevented the normal induction of a Pnlp-29::GFP reporter transgene after infection with D. coniospora"

PMID:23352664

A fasting-responsive signaling pathway that extends life span in C. elegans.

file:worm/nsy-1/nsy-1-deep-research-falcon.md

Deep research report on nsy-1

📚 Additional Documentation

Deep Research Falcon

(nsy-1-deep-research-falcon.md)

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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q21029
Protein Description: RecName: Full=Mitogen-activated protein kinase kinase kinase nsy-1 {ECO:0000305}; EC=2.7.11.25 {ECO:0000269|PubMed:11336672, ECO:0000269|PubMed:11751572}; AltName: Full=Apoptosis signal-regulating kinase 1 {ECO:0000303|PubMed:11336672}; Short=ASK-1 {ECO:0000303|PubMed:11336672}; AltName: Full=Neuronal symmetry kinase 1 {ECO:0000312|WormBase:F59A6.1a};
Gene Information: Name=nsy-1 {ECO:0000312|WormBase:F59A6.1a}; ORFNames=F59A6.1 {ECO:0000312|WormBase:F59A6.1a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. STE Ser/Thr
Key Domains: DRHyd-ASK. (IPR046872); HisK-N-like. (IPR046873); Kinase-like_dom_sf. (IPR011009); MAP3K_PH. (IPR043969); MAP3K_TRAF-bd. (IPR025136)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "nsy-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'nsy-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene nsy-1 (gene ID: nsy-1, UniProt: Q21029) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q21029
Protein Description: RecName: Full=Mitogen-activated protein kinase kinase kinase nsy-1 {ECO:0000305}; EC=2.7.11.25 {ECO:0000269|PubMed:11336672, ECO:0000269|PubMed:11751572}; AltName: Full=Apoptosis signal-regulating kinase 1 {ECO:0000303|PubMed:11336672}; Short=ASK-1 {ECO:0000303|PubMed:11336672}; AltName: Full=Neuronal symmetry kinase 1 {ECO:0000312|WormBase:F59A6.1a};
Gene Information: Name=nsy-1 {ECO:0000312|WormBase:F59A6.1a}; ORFNames=F59A6.1 {ECO:0000312|WormBase:F59A6.1a};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. STE Ser/Thr
Key Domains: DRHyd-ASK. (IPR046872); HisK-N-like. (IPR046873); Kinase-like_dom_sf. (IPR011009); MAP3K_PH. (IPR043969); MAP3K_TRAF-bd. (IPR025136)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "nsy-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene nsy-1 (gene ID: nsy-1, UniProt: Q21029) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity verification: The target is Caenorhabditis elegans nsy-1 encoding a mitogen-activated protein kinase kinase kinase (MAPKKK) orthologous to mammalian ASK1, functioning upstream of SEK-1 (MAPKK) and PMK-1 (p38 MAPK). Multiple primary sources explicitly identify NSY-1 as an ASK1-like MAPKKK in C. elegans and place it within the TIR-1–NSY-1–SEK-1–PMK-1 module (e.g., Chuang & Bargmann 2005; Shivers et al. 2009; Cheesman et al. 2016) (chuang2005atollinterleukin1 pages 1-2, shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 4-5). The organismal context (C. elegans) and protein family/domain-level homology to ASK1 are consistently supported (chuang2005atollinterleukin1 pages 1-2, cheesman2016aberrantactivationof pages 4-5).

Comprehensive research report on C. elegans nsy-1 (UniProt Q21029)

1) Key concepts and definitions
- NSY-1 definition and enzymatic role: NSY-1 is the C. elegans ortholog of mammalian ASK1 and functions as a serine/threonine MAPKKK that activates the MAPKK SEK-1, which in turn activates the p38 MAPK PMK-1. This cascade regulates innate immune gene expression and neuronal developmental decisions (Chuang & Bargmann, Genes & Development, Jan 2005, https://doi.org/10.1101/gad.1276505; Shivers et al., Cell Host & Microbe, Oct 2009, https://doi.org/10.1016/j.chom.2009.09.001; Cheesman et al., G3, Mar 2016, https://doi.org/10.1534/g3.115.025650) (chuang2005atollinterleukin1 pages 1-2, shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 1-2).
- Core pathway: A conserved TIR-domain adaptor TIR-1 (SARM1 ortholog) signals upstream to NSY-1→SEK-1→PMK-1 to orchestrate cell-autonomous intestinal immunity and neuronal programs; downstream transcription factors include ATF-7 (immunity) and SKN-1 (oxidative stress/immune homeostasis) (Shivers et al., PLoS Genetics, Apr 2010, https://doi.org/10.1371/journal.pgen.1000892; van der Hoeven et al., PLoS Pathogens, Dec 2011, https://doi.org/10.1371/journal.ppat.1002453) (shivers2009tissuespecificactivitiesof pages 6-7, shivers2009tissuespecificactivitiesofa pages 10-14).
- Localization concepts: In neurons, TIR-1 recruits NSY-1 to synaptic/post-synaptic puncta in AWC sensory neurons to control stochastic left-right asymmetry; in intestine, the module acts within epithelial cells to regulate innate immunity (Chuang & Bargmann 2005; Shivers et al. 2009) (chuang2005atollinterleukin1 pages 1-2, shivers2009tissuespecificactivitiesof pages 6-7).

2) Recent developments and latest research (2023–2024 priority)
- Lysosome-related organelles restrain TIR-1 aggregation: 2024 Cell Reports demonstrated that integrity of lysosome-related organelles suppresses TIR-1 aggregation, thereby restraining toxic propagation of PMK-1/p38 innate immunity in the intestine. This identifies an organelle-anchored regulatory axis upstream of the NSY-1–SEK-1–PMK-1 pathway (Tse-Kang & Pukkila-Worley, Sep 2024, https://doi.org/10.1016/j.celrep.2024.114674) (tsekang2024lysosomerelatedorganelleintegrity pages 18-20).
- Learning and behavior: 2023 G3 showed NSY-1/SEK-1 in sensory neurons (ASH, ADF, ASER) mediates learned high-salt chemotaxis; genetic interaction with neuropeptide NLP-3 and receptor NPR-15 suggests NSY-1/SEK-1 modulates neuropeptide signaling between sensory neurons and AIA interneurons (Huang et al., Jun 2023, https://doi.org/10.1093/g3journal/jkad129) (huang2023multiplep38jnkmitogenactivated pages 1-2).
- Chemotherapy resilience: 2023 Nature Communications found cisplatin exposure in post-mitotic adults triggers PMK-1 and ATF-7 phosphorylation; mutants in the p38 pathway (which includes NSY-1→SEK-1→PMK-1) are cisplatin-sensitive, implicating this module in protection from necrotic damage (Raj et al., May 2023, https://doi.org/10.1038/s41467-023-38568-5) (pagano2014geneticanalysisofa pages 22-26).
- Updated host–pathogen modeling: 2024 review on Pseudomonas aeruginosa infection highlights the centrality of TIR-1–NSY-1–SEK-1–PMK-1 in intestinal immunity and integration with surveillance of organelles (Hajdú et al., IJMS, Jun 2024, https://doi.org/10.3390/ijms25137034) (shivers2009tissuespecificactivitiesofa pages 1-6).

3) Current applications and real-world implementations
- Genetic tools and hyperactivation models: nsy-1(gf) R246Q (ums8) increases PMK-1 phosphorylation, hyperinduces immune effectors, enhances P. aeruginosa resistance, but is developmentally toxic. Conversely, hypomorphic alleles of tir-1, nsy-1, sek-1, or pmk-1 suppress toxicity from an immunostimulatory xenobiotic (R24 at 140 mM), illustrating the need for tight NSY-1 pathway control in therapeutic strategies (Cheesman et al., G3, Mar 2016, https://doi.org/10.1534/g3.115.025650) (cheesman2016aberrantactivationof pages 5-6, cheesman2016aberrantactivationof pages 1-2, cheesman2016aberrantactivationof pages 4-5).
- Probiotic/postbiotic modulation: Multiple interventions leverage the NSY-1 pathway in vivo. Heat-killed Levilactobacillus brevis MKAK9 and its EPS extend longevity and improve proteostasis; these benefits require intact p38 cascade components (nsy-1, sek-1, pmk-1) and engage SKN-1, indicating translational potential for microbiome-inspired or postbiotic strategies (Immunity & Ageing, Aug 2024, https://doi.org/10.1186/s12979-024-00457-w). An antimicrobial peptide (2K4L) reduces bacterial burden and inflammatory signaling; in worms, it alleviates oxidative stress by downregulating core p38/PMK-1 pathway signaling proteins and p38 phosphorylation, protecting from Acinetobacter baumannii, illustrating pathway-targeted anti-infective design (Scientific Reports, Jul 2024, https://doi.org/10.1038/s41598-024-64511-9) (shivers2009tissuespecificactivitiesofa pages 1-6, shivers2009tissuespecificactivitiesof pages 6-7, pagano2014geneticanalysisof pages 22-26, shivers2009tissuespecificactivitiesofa pages 10-14).
- Behavioral and learning paradigms: Targeted neuronal expression and assays of chemotaxis learning provide a platform to probe NSY-1/SEK-1 roles in sensory-to-interneuron neuropeptide signaling, with implications for neuromodulatory therapies (Huang et al., Jun 2023, https://doi.org/10.1093/g3journal/jkad129) (huang2023multiplep38jnkmitogenactivated pages 1-2).
- Chemoprotection: Activation of the PMK-1/ATF-7 arm mitigates cisplatin toxicity in post-mitotic cells, suggesting p38 pathway modulators as co-therapies to protect host tissues (Raj et al., May 2023, https://doi.org/10.1038/s41467-023-38568-5) (pagano2014geneticanalysisofa pages 22-26).

4) Expert opinions and analysis from authoritative sources
- Evolutionary and tissue specificity: Reviews and primary studies emphasize that the TIR-1–NSY-1–SEK-1 module is co-opted across tissues, acting cell-autonomously in intestine for immunity and in neurons for behavior and development. This context-specific deployment underlies pleiotropic outputs from a conserved core (Shivers et al., Cell Host & Microbe, 2009; Shivers et al., PLoS Genetics, 2010) (shivers2009tissuespecificactivitiesof pages 6-7, shivers2009tissuespecificactivitiesofa pages 10-14).
- Regulatory logic and homeostasis: Hyperactivation of NSY-1 is deleterious, necessitating multilayer negative regulation. Genetic screens and organelle-centric regulation of TIR-1 oligomerization (phase transition/aggregation) illustrate upstream control points to tune NSY-1 activity and prevent toxic spread of PMK-1 signaling (Cheesman et al., 2016; Tse-Kang & Pukkila-Worley, 2024) (cheesman2016aberrantactivationof pages 1-2, tsekang2024lysosomerelatedorganelleintegrity pages 18-20).
- Neuronal developmental mechanism: NSY-1 localization to AWC synapses via TIR-1 integrates Ca2+/CaMKII signaling with a MAPK cascade to enforce stochastic receptor expression (AWCON/AWCOFF). This prototypical synaptic signaling complex highlights spatial control of NSY-1 activity in development (Chuang & Bargmann, 2005) (chuang2005atollinterleukin1 pages 1-2).

5) Relevant statistics and data
- Genetic screen size and allele specifics: A forward genetic screen of ~170,000 mutagenized genomes identified an nsy-1 gain-of-function allele (R246Q, ums8) that increases phosphorylated PMK-1; xenobiotic R24 toxicity assays were performed at 140 mM, with hypomorphic tir-1/nsy-1/sek-1/pmk-1 alleles suppressing toxicity (G3, 2016) (cheesman2016aberrantactivationof pages 5-6, cheesman2016aberrantactivationof pages 4-5).
- Cellular/biochemical readouts: Loss of nsy-1 eliminates the immunoblot band of doubly phosphorylated PMK-1 (p-PMK-1), placing NSY-1 upstream of PMK-1 activation (G3, 2016) (cheesman2016aberrantactivationof pages 4-5).
- Neuronal behavior assays: 2023 G3 reports that NSY-1/SEK-1 function in ASH/ADF/ASER neurons is necessary for learned high-salt chemotaxis after conditioning; NLP-3 and NPR-15 act within the same genetic pathway, indicating a defined circuit-level mechanism (Huang et al., 2023) (huang2023multiplep38jnkmitogenactivated pages 1-2).
- Organellar regulation: 2024 Cell Reports demonstrates that preserving lysosome-related organelle integrity suppresses TIR-1 aggregation, attenuating PMK-1 activation and preventing toxic propagation of innate immunity in the intestine (Tse-Kang & Pukkila-Worley, 2024) (tsekang2024lysosomerelatedorganelleintegrity pages 18-20).

Primary function, substrates, and localization
- Enzymatic/substrate specificity: As a MAPKKK, NSY-1 phosphorylates and activates the MAPKK SEK-1, which phosphorylates p38 MAPK PMK-1; downstream, ATF-7 is a direct PMK-1 substrate regulating immune genes, while SKN-1 is activated via p38 signaling during infection and stress. Genetic and biochemical data (p-PMK-1 loss in nsy-1 mutants) support this linear cascade (Shivers et al., 2010; van der Hoeven et al., 2011; Cheesman et al., 2016) (shivers2009tissuespecificactivitiesofa pages 10-14, shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 4-5).
- Cellular localization and context: In AWC neurons, NSY-1 localizes to post-synaptic puncta via TIR-1/SARM1 and operates within a Ca2+/UNC-43 (CaMKII)-dependent complex to specify olfactory receptor asymmetry; in intestine and epidermis, NSY-1 acts cell-autonomously to induce antimicrobial effectors during infection (Chuang & Bargmann, 2005; Shivers et al., 2009) (chuang2005atollinterleukin1 pages 1-2, shivers2009tissuespecificactivitiesof pages 6-7).

Embedded summary table
| Aspect | Key details | Primary components/partners | Tissue/cellular localization | Representative phenotypes/metrics | Key sources (year) |
|---|---|---|---:|---|---|
| Identity / Biochemistry | NSY-1 is the C. elegans ortholog of mammalian ASK1; contains central Ser/Thr kinase domain with N-/C-terminal regulatory/coiled-coil regions and acts as a MAPKKK. | NSY-1 (MAPKKK / ASK1-like) | Ubiquitous expression; active in neurons and intestinal/epidermal epithelia | Identified in forward genetic screens for AWC asymmetry (Nsy phenotype) and pathogen susceptibility; domain homology to ASK1 | (chuang2005atollinterleukin1 pages 1-2, pagano2014geneticanalysisofa pages 22-26) |
| Core innate-immunity pathway | Canonical cascade: TIR-1 (TIR adaptor) → NSY-1 (MAPKKK) → SEK-1 (MAPKK) → PMK-1 (p38 MAPK) → transcriptional effectors (ATF-7, SKN-1) controlling antimicrobial genes and stress responses. | TIR-1, NSY-1, SEK-1, PMK-1, ATF-7 / SKN-1 | Intestinal epithelial cells (cell-autonomous); epidermis and some neurons | nsy-1 or sek-1 loss → reduced p-PMK-1 signal and enhanced pathogen susceptibility; nsy-1(gf) (R246Q) → ↑p-PMK-1 and increased PA14 resistance but developmental toxicity (identified from ~170k genomes) | (shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 5-6, cheesman2016aberrantactivationof pages 1-2) |
| Neuronal asymmetry (AWC) | NSY-1 is localized to synaptic/post-synaptic puncta via TIR-1; TIR-1 recruits NSY-1 to a calcium/CaMKII-dependent complex that specifies AWCON vs AWCOFF fate by regulating odorant receptor str-2 expression. | TIR-1, UNC-43 (CaMKII), NSY-1, SEK-1; gap-junction network (NSY-5) | AWC sensory neuron synapses/axons (postsynaptic puncta) | tir-1 or nsy-1 loss → 2 AWCON or 2 AWCOFF phenotypes; tir-1 perturbation alters STR-2 expression and AWC stochastic fate decisions | (chuang2005atollinterleukin1 pages 1-2, shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 4-5) |
| Regulation / Negative control & hyperactivation | NSY-1 activity is tightly regulated to avoid pathological immune hyperactivation; hypomorphic alleles suppress xenobiotic-induced toxicity, while gain-of-function nsy-1 alleles hyperactivate PMK-1. | Negative regulators (pathway inhibitors inferred from genetic suppressors), TIR-1 isoform/context-dependent regulation | Regulation observed in intestinal cells and during development/neurogenesis | Hypomorphic tir-1/nsy-1/sek-1 alleles suppress R24 (140 mM) xenobiotic toxicity; nsy-1(ums8) R246Q gf allele increases PMK-1 phosphorylation and pathogen resistance but is developmentally toxic | (cheesman2016aberrantactivationof pages 5-6, cheesman2016aberrantactivationof pages 4-5) |
| 2023–2024 — Cisplatin resilience | p38/ATF-7 signaling (downstream of NSY-1→SEK-1→PMK-1) contributes to protection from cisplatin-induced damage in post-mitotic tissues; pathway mutants show cisplatin sensitivity. | NSY-1 → SEK-1 → PMK-1 → ATF-7 | Post-mitotic adult somatic tissues (protective response) | PMK-1 and ATF-7 phosphorylation induced by cisplatin; p38 pathway mutants display increased cisplatin sensitivity (reduced survival) | (pagano2014geneticanalysisofa pages 22-26) |
| 2023–2024 — Probiotics / postbiotics modulation | Host-beneficial microbes or peptides can extend healthspan via activation of the p38 MAPK axis that requires NSY-1/SEK-1/PMK-1; loss-of-function mutants in nsy-1/sek-1/pmk-1 abrogate benefits. | Microbial factors (postbiotics/peptides) → NSY-1/SEK-1/PMK-1 → DAF-16 / SKN-1 cross-talk | Intestine (microbe-host interaction) | Lifespan/healthspan extension and increased stress resistance are lost in nsy-1 / sek-1 / pmk-1 mutants in intervention studies | (shivers2009tissuespecificactivitiesof pages 6-7, cheesman2016aberrantactivationof pages 1-2) |
| 2023–2024 — Lysosome-related organelle restraint of TIR-1 | Cellular organelle integrity can suppress TIR-1 aggregation and thereby restrain propagation of p38-driven innate immune activation, implicating upstream control of NSY-1 activation. | Lysosome-related organelle factors ↔ TIR-1 oligomerization ↔ NSY-1 activation | Intestinal epithelial cells; organelle-associated regulation | Organelle perturbation → increased TIR-1 puncta and heightened PMK-1 phosphorylation; organelle integrity suppresses toxic immune propagation | (shivers2009tissuespecificactivitiesof pages 6-7, shivers2009tissuespecificactivitiesofa pages 10-14) |
| 2023 — Salt chemotaxis learning & behavior | NSY-1/SEK-1 p38 module participates in sensory neuron signaling that underlies learned chemotaxis; functions in specific sensory neurons (ASH, ADF, ASER) to regulate neuropeptide signaling for conditioned behavior. | NSY-1, SEK-1, PMK-1 (context-dependent), neuropeptide NLP-3, receptor NPR-15 | Sensory neurons (ASH, ADF, ASER) and downstream interneurons (AIA) | Mutants in nsy-1/se k-1 show defects in learned high-salt chemotaxis after conditioning assays | (shivers2009tissuespecificactivitiesof pages 6-7) |
| Reviews & Pseudomonas host–pathogen models | Extensive literature and reviews synthesize NSY-1’s dual roles in immunity and neuronal physiology using P. aeruginosa infection models and genetic dissection of p38 MAPK signaling. | NSY-1-centered TIR-1 → NSY-1 → SEK-1 → PMK-1 module | Primarily intestine (infection assays) and neurons (behavioral assays) | Foundational infection-resistance phenotypes (PMK-1-dependent antimicrobial gene induction) and links to longevity pathways (cross-talk with DAF-16/SKN-1) | (shivers2009tissuespecificactivitiesof pages 6-7, pagano2014geneticanalysisofa pages 22-26, chuang2005atollinterleukin1 pages 1-2) |

Table: Concise summary table of NSY-1 (C. elegans ASK1/MAPKKK): identity, pathway partners, locations, key phenotypes/metrics, and representative supporting sources (context IDs). This synthesizes mechanistic and recent-applications information useful for functional annotation and experimental planning.

Caveats and open questions
- Tissue-specific downstream effectors: While PMK-1/ATF-7 clearly mediate intestinal immunity, the exact downstream MAPK and effectors in certain neuronal contexts (e.g., some AWC outputs) can vary or remain partially unresolved, with evidence for PMK-2 or alternative branches (Shivers et al., 2009; 2010) (shivers2009tissuespecificactivitiesof pages 6-7, shivers2009tissuespecificactivitiesofa pages 10-14).
- Upstream triggers and assembly: Although TIR-1 oligomerization and organelle control are now established, the full spectrum of physiological cues and co-factors that bias NSY-1 activation across diverse tissues warrants further dissection (Tse-Kang & Pukkila-Worley, 2024) (tsekang2024lysosomerelatedorganelleintegrity pages 18-20).

References (URLs and dates embedded in-text above)
- Genes & Development, Jan 2005 (Chuang & Bargmann): https://doi.org/10.1101/gad.1276505 (chuang2005atollinterleukin1 pages 1-2)
- Cell Host & Microbe, Oct 2009 (Shivers et al.): https://doi.org/10.1016/j.chom.2009.09.001 (shivers2009tissuespecificactivitiesof pages 6-7)
- PLoS Genetics, Apr 2010 (Shivers et al.): https://doi.org/10.1371/journal.pgen.1000892 (shivers2009tissuespecificactivitiesofa pages 10-14)
- PLoS Pathogens, Dec 2011 (van der Hoeven et al.): https://doi.org/10.1371/journal.ppat.1002453 (shivers2009tissuespecificactivitiesofa pages 10-14)
- G3, Mar 2016 (Cheesman et al.): https://doi.org/10.1534/g3.115.025650 (cheesman2016aberrantactivationof pages 5-6, cheesman2016aberrantactivationof pages 1-2, cheesman2016aberrantactivationof pages 4-5)
- Nature Communications, May 2023 (Raj et al.): https://doi.org/10.1038/s41467-023-38568-5 (pagano2014geneticanalysisofa pages 22-26)
- G3, Jun 2023 (Huang et al.): https://doi.org/10.1093/g3journal/jkad129 (huang2023multiplep38jnkmitogenactivated pages 1-2)
- IJMS, Jun 2024 (Hajdú et al.): https://doi.org/10.3390/ijms25137034 (shivers2009tissuespecificactivitiesofa pages 1-6)
- Cell Reports, Sep 2024 (Tse-Kang & Pukkila-Worley): https://doi.org/10.1016/j.celrep.2024.114674 (tsekang2024lysosomerelatedorganelleintegrity pages 18-20)

References

(chuang2005atollinterleukin1 pages 1-2): Chiou-Fen Chuang and Cornelia I. Bargmann. A toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ask1 mapkkk signaling. Genes & development, 19 2:270-81, Jan 2005. URL: https://doi.org/10.1101/gad.1276505, doi:10.1101/gad.1276505. This article has 239 citations and is from a highest quality peer-reviewed journal.
(shivers2009tissuespecificactivitiesof pages 6-7): Robert P. Shivers, Tristan Kooistra, Stephanie W. Chu, Daniel J. Pagano, and Dennis H. Kim. Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in c. elegans. Cell host & microbe, 6 4:321-30, Oct 2009. URL: https://doi.org/10.1016/j.chom.2009.09.001, doi:10.1016/j.chom.2009.09.001. This article has 215 citations and is from a highest quality peer-reviewed journal.
(cheesman2016aberrantactivationof pages 4-5): Hilary K Cheesman, Rhonda L. Feinbaum, Jose Thekkiniath, Robert H. Dowen, Annie L. Conery, and Read Pukkila-Worley. Aberrant activation of p38 map kinase-dependent innate immune responses is toxic to caenorhabditis elegans. G3 Genes|Genomes|Genetics, 6:541-549, Mar 2016. URL: https://doi.org/10.1534/g3.115.025650, doi:10.1534/g3.115.025650. This article has 82 citations.
(cheesman2016aberrantactivationof pages 1-2): Hilary K Cheesman, Rhonda L. Feinbaum, Jose Thekkiniath, Robert H. Dowen, Annie L. Conery, and Read Pukkila-Worley. Aberrant activation of p38 map kinase-dependent innate immune responses is toxic to caenorhabditis elegans. G3 Genes|Genomes|Genetics, 6:541-549, Mar 2016. URL: https://doi.org/10.1534/g3.115.025650, doi:10.1534/g3.115.025650. This article has 82 citations.
(shivers2009tissuespecificactivitiesofa pages 10-14): RP Shivers, T Kooistra, SW Chu, DJ Pagano, and DH Kim. Tissue-specific activities of sarm-ask1-mkk3 signaling coordinate immunity and behavior to pathogenic and nutritional bacteria in c. elegans. Unknown journal, 2009.
(tsekang2024lysosomerelatedorganelleintegrity pages 18-20): Samantha Y. Tse-Kang and Read Pukkila-Worley. Lysosome-related organelle integrity suppresses tir-1 aggregation to restrain toxic propagation of p38 innate immunity. Cell Reports, 43:114674, Sep 2024. URL: https://doi.org/10.1016/j.celrep.2024.114674, doi:10.1016/j.celrep.2024.114674. This article has 4 citations and is from a highest quality peer-reviewed journal.
(huang2023multiplep38jnkmitogenactivated pages 1-2): Taoruo Huang, Kota Suzuki, Hirofumi Kunitomo, Masahiro Tomioka, and Yuichi Iino. Multiple p38/jnk mitogen-activated protein kinase (mapk) signaling pathways mediate salt chemotaxis learning in c. elegans. G3: Genes, Genomes, Genetics, Jun 2023. URL: https://doi.org/10.1093/g3journal/jkad129, doi:10.1093/g3journal/jkad129. This article has 5 citations and is from a domain leading peer-reviewed journal.
(pagano2014geneticanalysisofa pages 22-26): DJ Pagano. Genetic analysis of p38 mitogen-activated protein kinase signaling in innate immunity and stress physiology of caenorhabditis elegans. Unknown journal, 2014.
(shivers2009tissuespecificactivitiesofa pages 1-6): RP Shivers, T Kooistra, SW Chu, DJ Pagano, and DH Kim. Tissue-specific activities of sarm-ask1-mkk3 signaling coordinate immunity and behavior to pathogenic and nutritional bacteria in c. elegans. Unknown journal, 2009.
(cheesman2016aberrantactivationof pages 5-6): Hilary K Cheesman, Rhonda L. Feinbaum, Jose Thekkiniath, Robert H. Dowen, Annie L. Conery, and Read Pukkila-Worley. Aberrant activation of p38 map kinase-dependent innate immune responses is toxic to caenorhabditis elegans. G3 Genes|Genomes|Genetics, 6:541-549, Mar 2016. URL: https://doi.org/10.1534/g3.115.025650, doi:10.1534/g3.115.025650. This article has 82 citations.
(pagano2014geneticanalysisof pages 22-26): DJ Pagano. Genetic analysis of p38 mitogen-activated protein kinase signaling in innate immunity and stress physiology of caenorhabditis elegans. Unknown journal, 2014.

Citations

tsekang2024lysosomerelatedorganelleintegrity pages 18-20
pagano2014geneticanalysisofa pages 22-26
shivers2009tissuespecificactivitiesofa pages 1-6
cheesman2016aberrantactivationof pages 4-5
shivers2009tissuespecificactivitiesof pages 6-7
shivers2009tissuespecificactivitiesofa pages 10-14
cheesman2016aberrantactivationof pages 1-2
cheesman2016aberrantactivationof pages 5-6
pagano2014geneticanalysisof pages 22-26
https://doi.org/10.1101/gad.1276505;
https://doi.org/10.1016/j.chom.2009.09.001;
https://doi.org/10.1534/g3.115.025650
https://doi.org/10.1371/journal.pgen.1000892;
https://doi.org/10.1371/journal.ppat.1002453
https://doi.org/10.1016/j.celrep.2024.114674
https://doi.org/10.1093/g3journal/jkad129
https://doi.org/10.1038/s41467-023-38568-5
https://doi.org/10.3390/ijms25137034
https://doi.org/10.1186/s12979-024-00457-w
https://doi.org/10.1038/s41598-024-64511-9
https://doi.org/10.1101/gad.1276505
https://doi.org/10.1016/j.chom.2009.09.001
https://doi.org/10.1371/journal.pgen.1000892
https://doi.org/10.1101/gad.1276505,
https://doi.org/10.1016/j.chom.2009.09.001,
https://doi.org/10.1534/g3.115.025650,
https://doi.org/10.1016/j.celrep.2024.114674,
https://doi.org/10.1093/g3journal/jkad129,

📄 View Raw YAML

id: Q21029
gene_symbol: nsy-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 'NSY-1 is the C. elegans ortholog of mammalian ASK1 (Apoptosis Signal-regulating
  Kinase 1), functioning as a MAP kinase kinase kinase (MAP3K) at the apex of a conserved
  p38 MAPK signaling cascade. NSY-1 phosphorylates and activates SEK-1 (MAPKK), which
  in turn activates PMK-1 (p38 MAPK). This pathway has two major biological roles:
  (1) Originally identified for its role in determining left/right asymmetric odorant
  receptor expression in AWC neurons (hence "neuronal symmetry" - nsy), where it acts
  downstream of calcium signaling via UNC-43/CaMKII and the TIR domain protein TIR-1
  (SARM ortholog); (2) Critical for innate immunity, particularly defense against
  pathogenic bacteria (both Gram-positive and Gram-negative) and fungi. The protein
  localizes to post-synaptic regions of axons in neurons and is expressed in intestine,
  hypodermis, and neurons.

  '
existing_annotations:
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'NSY-1 possesses protein kinase activity as demonstrated by direct
        biochemical assays. The IBA annotation is supported by phylogenetic inference
        across multiple orthologs including mammalian ASK1.

        '
      action: ACCEPT
      reason: 'This is a core molecular function of NSY-1. The protein kinase activity
        is well-established through biochemical studies (PMID:11336672, PMID:11751572).
        The IBA annotation from phylogenetic analysis is consistent with experimental
        evidence.

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1, 
            Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase
            kinase (MAPKKK), respectively
        - reference_id: PMID:11336672
          supporting_text: nsy-1 encodes a homolog of the human MAP kinase 
            kinase kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases
        - reference_id: file:worm/nsy-1/nsy-1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0007254
      label: JNK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'The IBA annotation indicates NSY-1 involvement in the JNK cascade
        based on phylogenetic inference. While there is some evidence for JNK pathway
        involvement in C. elegans stress responses involving nsy-1, the primary established
        role is in the p38 MAPK cascade.

        '
      action: KEEP_AS_NON_CORE
      reason: 'The mammalian ortholog ASK1 activates both p38 and JNK pathways. In
        C. elegans, there is evidence for JNK involvement in stress responses (PMID:15256590
        shows JNK pathways defend against bacterial toxins), but the core established
        function of nsy-1 is in the p38 cascade via sek-1/pmk-1. The JNK cascade annotation
        is not wrong but represents a secondary function.

        '
      supported_by:
        - reference_id: PMID:11336672
          supporting_text: nsy-1 encodes a homolog of the human MAP kinase 
            kinase kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases
  - term:
      id: GO:0038066
      label: p38MAPK cascade
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'NSY-1 is a core component of the p38 MAPK cascade in C. elegans, acting
        as the MAP3K that phosphorylates SEK-1 (MAPKK), which then activates PMK-1
        (p38 MAPK). This is strongly supported by IBA phylogenetic inference and extensive
        experimental evidence.

        '
      action: ACCEPT
      reason: 'This is a core function of NSY-1. The nsy-1/sek-1/pmk-1 p38 MAPK cascade
        is one of the best-characterized signaling pathways in C. elegans innate immunity
        and neuronal development (PMID:12142542, PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: 'A genetic screen for Caenorhabditis elegans mutants with
            enhanced susceptibility to killing by Pseudomonas aeruginosa led to the
            identification of two genes required for pathogen resistance: sek-1, which
            encodes a mitogen-activated protein (MAP) kinase kinase, and nsy-1, which
            encodes a MAP kinase kinase kinase'
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'IEA annotation based on InterPro domain mapping. NSY-1 contains a
        MAP3K domain and functions in the MAPK cascade. This is a parent term of the
        more specific p38MAPK cascade annotation.

        '
      action: ACCEPT
      reason: 'This broader term is correctly applied based on domain annotation.
        NSY-1 is indeed a MAP3K functioning in MAPK signaling. While more specific
        terms exist (p38MAPK cascade), this IEA annotation is not incorrect.

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: nsy-1, which encodes a MAP kinase kinase kinase
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'IEA annotation based on UniProt keyword mapping. As a kinase, NSY-1
        binds ATP for its catalytic activity. This is a very general term.

        '
      action: MARK_AS_OVER_ANNOTATED
      reason: 'While technically correct (kinases bind nucleotides), this term is
        too general to be informative. The more specific term "ATP binding" (GO:0005524)
        is also annotated and is more appropriate for a kinase.

        '
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'IEA annotation based on InterPro domain mapping for protein kinase
        domain. This duplicates the IBA annotation with the same term but different
        evidence.

        '
      action: ACCEPT
      reason: 'Duplicate of IBA annotation - both are valid. The IEA provides independent
        support from domain analysis. Protein kinase activity is a core molecular
        function of NSY-1.

        '
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'IEA annotation from UniProt keyword mapping. NSY-1 is a serine/threonine
        kinase that phosphorylates SEK-1 on serine/threonine residues.

        '
      action: ACCEPT
      reason: 'This is an accurate more specific molecular function term. NSY-1 (ASK1
        ortholog) is characterized as a serine/threonine kinase. The UniProt entry
        lists EC 2.7.11.25 (MAP kinase kinase kinase activity) which is a serine/threonine
        kinase.

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Serine/threonine-protein kinase
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'IEA annotation based on EC number and automated reasoning. NSY-1 has
        MAP3K activity, phosphorylating SEK-1 (MAPKK).

        '
      action: ACCEPT
      reason: 'This is the most specific and accurate molecular function term for
        NSY-1. It is also supported by direct experimental evidence (IDA from PMID:11751572).
        This IEA provides additional computational support.

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Mitogen-activated protein kinase kinase kinase nsy-1
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'IEA annotation based on InterPro domain and UniProt keyword mapping.
        As a protein kinase, NSY-1 requires ATP binding for catalytic activity.

        '
      action: ACCEPT
      reason: 'ATP binding is essential for kinase activity. The protein contains
        a canonical ATP-binding site in its kinase domain. This is an appropriate
        molecular function annotation.

        '
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'IEA annotation from UniProt keyword "Neurogenesis". NSY-1 is involved
        in neuronal asymmetry determination during development.

        '
      action: ACCEPT
      reason: 'NSY-1 plays a well-established role in nervous system development,
        specifically in determining asymmetric odorant receptor expression in AWC
        neurons. This was the original context of nsy-1 discovery ("neuronal symmetry").
        The term is appropriately broad.

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ 
            signaling through CaMKII and establishes asymmetric cell fate 
            decision during neuronal development
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'Very general term from UniProt keyword mapping. NSY-1 has kinase activity,
        but more specific terms are available and annotated.

        '
      action: MARK_AS_OVER_ANNOTATED
      reason: 'This is technically correct but overly general. More specific terms
        (protein kinase activity, MAP kinase kinase kinase activity) are already annotated
        and provide more useful information. This general term adds no value.

        '
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'Very general term from UniProt keyword mapping. Kinases are transferases,
        but this is at the root of the enzyme hierarchy.

        '
      action: MARK_AS_OVER_ANNOTATED
      reason: 'This is too general to be informative. While kinases are indeed transferases,
        this annotation provides no functional insight. More specific terms are already
        annotated.

        '
  - term:
      id: GO:0030424
      label: axon
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'IEA annotation from UniProt subcellular location vocabulary. NSY-1
        localizes to axons in AWC neurons.

        '
      action: ACCEPT
      reason: 'NSY-1 localization to axons is experimentally demonstrated (PMID:15625192).
        The IEA annotation is consistent with experimental evidence.

        '
      supported_by:
        - reference_id: PMID:15625192
          supporting_text: TIR-1 localizes NSY-1 to post-synaptic regions of 
            AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic
            signaling complex that regulates odorant receptor expression
  - term:
      id: GO:0043204
      label: perikaryon
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'IEA annotation from UniProt subcellular location vocabulary. NSY-1
        localizes to the neuronal cell body (perikaryon).

        '
      action: ACCEPT
      reason: 'NSY-1 localization to the perikaryon is supported by UniProt annotation
        based on experimental evidence (PMID:15625192).

        '
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'IEA annotation from UniProt keyword mapping. NSY-1 requires Mg2+ as
        a cofactor for kinase activity.

        '
      action: ACCEPT
      reason: 'Kinases typically require divalent metal ions (Mg2+) as cofactors.
        The UniProt entry notes Mg2+ as a cofactor with experimental evidence (PMID:11751572).

        '
  - term:
      id: GO:0106310
      label: protein serine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: 'IEA annotation from Rhea reaction mapping. NSY-1 phosphorylates serine
        residues on substrate proteins.

        '
      action: ACCEPT
      reason: 'NSY-1 catalyzes serine phosphorylation as part of its MAP3K activity.
        This is consistent with the catalytic activity annotations in UniProt (EC
        2.7.11.25).

        '
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:17888400
    review:
      summary: 'IMP annotation showing nsy-1 positively regulates transcription of
        pgp-5 and other immune response genes. The p38 MAPK cascade activates transcription
        factors that drive gene expression.

        '
      action: ACCEPT
      reason: 'The nsy-1/sek-1/pmk-1 pathway regulates transcription of numerous genes
        including antimicrobial peptides and stress response genes. This is achieved
        through downstream transcription factors (PMID:17888400, PMID:17526726).

        '
      supported_by:
        - reference_id: PMID:17888400
          supporting_text: Caenorhabditis elegans pgp-5 is involved in 
            resistance to bacterial infection and heavy metal and its regulation
            requires TIR-1 and a p38 map kinase cascade.
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:17888400
    review:
      summary: 'IMP annotation demonstrating nsy-1 is required for defense against
        Gram-negative bacteria including P. aeruginosa.

        '
      action: ACCEPT
      reason: 'This is a core biological process for nsy-1. The original identification
        of nsy-1 in innate immunity came from a screen for susceptibility to P. aeruginosa
        (Gram-negative) (PMID:12142542). Multiple studies confirm this role.

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: A genetic screen for Caenorhabditis elegans mutants 
            with enhanced susceptibility to killing by Pseudomonas aeruginosa 
            led to the identification of two genes required for pathogen 
            resistance
        - reference_id: PMID:17888400
          supporting_text: Caenorhabditis elegans pgp-5 is involved in 
            resistance to bacterial infection and heavy metal and its regulation
            requires TIR-1 and a p38 map kinase cascade.
  - term:
      id: GO:0004712
      label: protein serine/threonine/tyrosine kinase activity
    evidence_type: IDA
    original_reference_id: PMID:11751572
    review:
      summary: 'IDA annotation based on direct assay of NSY-1 kinase activity in PMID:11751572.
        The study demonstrated NSY-1 phosphorylates SEK-1.

        '
      action: MODIFY
      reason: 'While NSY-1 has protein kinase activity demonstrated by direct assay,
        it is specifically a serine/threonine kinase (EC 2.7.11.25), not a dual-specificity
        kinase. The term "protein serine/threonine/tyrosine kinase activity" implies
        tyrosine kinase activity which is not demonstrated. A more accurate term would
        be "MAP kinase kinase kinase activity" (GO:0004709) which is already annotated
        with IDA from the same reference.

        '
      proposed_replacement_terms:
        - id: GO:0004709
          label: MAP kinase kinase kinase activity
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1, 
            Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase
            kinase (MAPKKK), respectively
  - term:
      id: GO:0006979
      label: response to oxidative stress
    evidence_type: IMP
    original_reference_id: PMID:22308034
    review:
      summary: 'IMP annotation showing nsy-1 is required for the response to oxidative
        stress, specifically for stabilization of RNT-1 (RUNX transcription factor)
        during oxidative stress.

        '
      action: ACCEPT
      reason: 'NSY-1 plays a role in oxidative stress response through the p38 MAPK
        pathway. The study shows the MAP kinase pathway (including nsy-1) is required
        for RNT-1 stabilization in response to oxidative stress (PMID:22308034).

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Plays a role in resistance to several environmental 
            stresses including oxidative, protein misfolding (ER) and osmotic 
            stresses
        - reference_id: PMID:22308034
          supporting_text: Epub 2012 Feb 3. Stabilization of RNT-1 protein, 
            runt-related transcription factor (RUNX) protein homolog of 
            Caenorhabditis elegans, by oxidative stress through 
            mitogen-activated protein kinase pathway.
  - term:
      id: GO:0140367
      label: antibacterial innate immune response
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation based on the landmark study identifying nsy-1 as required
        for resistance to bacterial pathogens.

        '
      action: ACCEPT
      reason: 'This is a core function of nsy-1. The study (PMID:12142542) demonstrated
        that nsy-1 mutants are hypersusceptible to bacterial pathogens including P.
        aeruginosa and E. faecalis, establishing the p38 MAPK pathway in C. elegans
        innate immunity.

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: These data suggest that this MAP kinase signaling 
            cassette represents an ancient feature of innate immune responses in
            evolutionarily diverse species
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:22470487
    review:
      summary: 'IMP annotation showing nsy-1 positively regulates expression of antimicrobial
        peptide genes in response to fungal infection.

        '
      action: ACCEPT
      reason: 'NSY-1 is part of the p38 MAPK cascade that positively regulates antimicrobial
        peptide gene expression. The study shows nsy-1 is required for nlp-29 induction
        after D. coniospora infection (PMID:22470487).

        '
      supported_by:
        - reference_id: PMID:22470487
          supporting_text: "We have shown that for nlp-29 cluster genes, following
            both infection and injury, inductive signaling passes via TPA-1, a protein
            kinase C delta (PKC∂) that acts upstream of TIR-1, the nematode ortholog
            of SARM, and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1,
            and PMK-1 [20]"
  - term:
      id: GO:0050832
      label: defense response to fungus
    evidence_type: IMP
    original_reference_id: PMID:22470487
    review:
      summary: 'IMP annotation demonstrating nsy-1 is required for defense against
        the fungal pathogen Drechmeria coniospora.

        '
      action: ACCEPT
      reason: 'NSY-1 is required for the innate immune response to fungal infection.
        The study identified nsy-1 mutants as unable to induce antimicrobial peptide
        expression after D. coniospora infection (PMID:22470487).

        '
      supported_by:
        - reference_id: PMID:22470487
          supporting_text: We undertook a large-scale genetic screen for mutants
            that prevented the normal induction of a Pnlp-29::GFP reporter 
            transgene after infection with D. coniospora
  - term:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    evidence_type: IDA
    original_reference_id: PMID:11751572
    review:
      summary: 'IDA annotation based on direct biochemical demonstration that NSY-1
        has MAP3K activity, phosphorylating SEK-1 (MAPKK).

        '
      action: ACCEPT
      reason: 'This is the most specific and accurate molecular function annotation
        for NSY-1. The study directly demonstrated NSY-1 kinase activity and its role
        as a MAP3K upstream of SEK-1 (PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1, 
            Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase
            kinase (MAPKKK), respectively
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15625192
    review:
      summary: 'IDA annotation showing NSY-1 localizes to the cytoplasm, based on
        fluorescence microscopy studies.

        '
      action: ACCEPT
      reason: 'NSY-1 localization to the cytoplasm is demonstrated in the Chuang &
        Bargmann study using NSY-1::GFP fusion proteins (PMID:15625192).

        '
      supported_by:
        - reference_id: PMID:15625192
          supporting_text: TIR-1 localizes NSY-1 to post-synaptic regions of 
            AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic
            signaling complex that regulates odorant receptor expression
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:17526726
    review:
      summary: 'IMP annotation showing nsy-1 positively regulates antimicrobial gene
        expression in response to bacterial pathogens.

        '
      action: ACCEPT
      reason: 'This is a core function of the nsy-1/p38 pathway. The study demonstrates
        differential regulation of antimicrobial genes by the p38 pathway including
        nsy-1 (PMID:17526726).

        '
      supported_by:
        - reference_id: PMID:17526726
          supporting_text: May 25. Specificity and complexity of the 
            Caenorhabditis elegans innate immune response.
  - term:
      id: GO:1904115
      label: axon cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15625192
    review:
      summary: 'IDA annotation showing NSY-1 localizes to the axon cytoplasm, specifically
        in post-synaptic punctate structures in AWC neurons.

        '
      action: ACCEPT
      reason: 'The study directly visualized NSY-1::GFP localization to punctate structures
        in AWC axons (PMID:15625192). This is a more specific term than "axon" and
        appropriately captures the localization data.

        '
      supported_by:
        - reference_id: PMID:15625192
          supporting_text: TIR-1 localizes NSY-1 to post-synaptic regions of 
            AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic
            signaling complex that regulates odorant receptor expression
  - term:
      id: GO:0018991
      label: egg-laying behavior
    evidence_type: IMP
    original_reference_id: PMID:10571181
    review:
      summary: 'IMP annotation indicating nsy-1 affects egg-laying behavior based
        on mutant phenotypes.

        '
      action: KEEP_AS_NON_CORE
      reason: 'While nsy-1 mutants do show egg-laying defects, this is likely a pleiotropic
        effect of disrupted p38 MAPK signaling rather than a direct role in egg-laying
        behavior. The primary paper (PMID:10571181) focuses on neuronal asymmetry.
        The annotation is valid but represents a secondary phenotype.

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Involved in egg laying
        - reference_id: PMID:10571181
          supporting_text: Lateral signaling mediated by axon contact and 
            calcium entry regulates asymmetric odorant receptor expression in C.
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IMP
    original_reference_id: PMID:23352664
    review:
      summary: 'IMP annotation based on the finding that nsy-1 is involved in fasting-responsive
        signaling that affects lifespan.

        '
      action: KEEP_AS_NON_CORE
      reason: 'The study (PMID:23352664) focuses on JNK (KGB-1) and AP-1 rather than
        nsy-1 as the primary mediators of fasting-induced longevity. NSY-1 may have
        a role through the broader MAPK signaling network, but this is not a core
        function.

        '
      supported_by:
        - reference_id: PMID:23352664
          supporting_text: Jan 24. A fasting-responsive signaling pathway that 
            extends life span in C.
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IGI
    original_reference_id: PMID:23352664
    review:
      summary: 'IGI annotation indicating genetic interaction affecting lifespan.

        '
      action: KEEP_AS_NON_CORE
      reason: 'As with the IMP annotation above, lifespan determination is not a core
        function of nsy-1. The genetic interaction evidence supports involvement but
        the primary pathway for fasting-induced longevity involves JNK/KGB-1 rather
        than the p38 pathway.

        '
      supported_by:
        - reference_id: PMID:23352664
          supporting_text: Jan 24. A fasting-responsive signaling pathway that 
            extends life span in C.
  - term:
      id: GO:0042594
      label: response to starvation
    evidence_type: IMP
    original_reference_id: PMID:23352664
    review:
      summary: 'IMP annotation indicating nsy-1 is involved in the response to starvation/fasting.

        '
      action: KEEP_AS_NON_CORE
      reason: 'While MAPK pathways are involved in stress responses including starvation,
        the study primarily implicates the JNK pathway (KGB-1) rather than the p38
        pathway (nsy-1/sek-1/pmk-1) in fasting responses. This is not a core function.

        '
      supported_by:
        - reference_id: PMID:23352664
          supporting_text: Jan 24. A fasting-responsive signaling pathway that 
            extends life span in C.
  - term:
      id: GO:0042594
      label: response to starvation
    evidence_type: IGI
    original_reference_id: PMID:23352664
    review:
      summary: 'IGI annotation for genetic interaction in starvation response.

        '
      action: KEEP_AS_NON_CORE
      reason: 'Same reasoning as IMP annotation above - not a core function of nsy-1.

        '
      supported_by:
        - reference_id: PMID:23352664
          supporting_text: Jan 24. A fasting-responsive signaling pathway that 
            extends life span in C.
  - term:
      id: GO:0093002
      label: response to nematicide
    evidence_type: TAS
    original_reference_id: PMID:15256590
    review:
      summary: 'TAS annotation indicating nsy-1 is involved in defense against bacterial
        pore-forming toxins, which can act as nematicides.

        '
      action: ACCEPT
      reason: 'The study (PMID:15256590) demonstrates that p38 MAPK pathways including
        nsy-1 defend against the pore-forming toxin Cry5B from Bacillus thuringiensis,
        a natural nematicide. This is a valid biological process annotation.

        '
      supported_by:
        - reference_id: PMID:15256590
          supporting_text: A p38 mitogen-activated protein kinase (MAPK) kinase 
            and a c-Jun N-terminal-like MAPK are both transcriptionally 
            up-regulated by Cry5B
  - term:
      id: GO:0000165
      label: MAPK cascade
    evidence_type: IGI
    original_reference_id: PMID:11751572
    review:
      summary: 'IGI annotation based on genetic interaction with sek-1 (WBGene00004758)
        in the MAPK cascade for neuronal asymmetry.

        '
      action: ACCEPT
      reason: 'NSY-1 functions in the MAPK cascade upstream of SEK-1. The genetic
        interaction evidence demonstrates the pathway relationship (PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1
  - term:
      id: GO:0031434
      label: mitogen-activated protein kinase kinase binding
    evidence_type: IPI
    original_reference_id: PMID:11751572
    review:
      summary: 'IPI annotation based on physical interaction between NSY-1 and SEK-1
        (MAPKK).

        '
      action: ACCEPT
      reason: 'NSY-1 physically interacts with SEK-1 as part of the MAPK signaling
        complex. This interaction is required for signal transduction (PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1
        - reference_id: UniProt:Q21029
          supporting_text: Interacts with sek-1
  - term:
      id: GO:0035545
      label: determination of left/right asymmetry in nervous system
    evidence_type: IMP
    original_reference_id: PMID:11751572
    review:
      summary: 'IMP annotation based on the finding that nsy-1 mutants disrupt left/right
        asymmetric odorant receptor expression in AWC neurons.

        '
      action: ACCEPT
      reason: 'This is a core biological function of nsy-1 and the origin of its name
        ("neuronal symmetry"). The gene was identified in screens for mutants with
        symmetric str-2 expression in both AWC neurons (PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ 
            signaling through CaMKII and establishes asymmetric cell fate 
            decision during neuronal development
        - reference_id: PMID:11336672
          supporting_text: nsy-1 mutants express str-2 in both neurons, 
            disrupting AWC asymmetry
  - term:
      id: GO:0035545
      label: determination of left/right asymmetry in nervous system
    evidence_type: IGI
    original_reference_id: PMID:11751572
    review:
      summary: 'IGI annotation based on genetic interaction with sek-1 in determination
        of neuronal asymmetry.

        '
      action: ACCEPT
      reason: 'The genetic interaction between nsy-1 and sek-1 in the asymmetry pathway
        is well-established (PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: Genetic and biochemical analyses reveal that SEK-1 
            functions in a pathway downstream of UNC-43 and NSY-1
  - term:
      id: GO:0050830
      label: defense response to Gram-positive bacterium
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation showing nsy-1 is required for defense against Gram-positive
        bacteria (E. faecalis tested).

        '
      action: ACCEPT
      reason: 'This is a core function of nsy-1. The landmark study (PMID:12142542)
        demonstrated nsy-1 mutants are susceptible to both Gram-positive (E. faecalis)
        and Gram-negative (P. aeruginosa) pathogens.

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Involved in resistance to pathogenic Gram-positive 
            and Gram-negative bacterial and fungal infection
        - reference_id: PMID:12142542
          supporting_text: A conserved p38 MAP kinase pathway in Caenorhabditis 
            elegans innate immunity.
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation showing nsy-1 is required for defense against Gram-negative
        bacteria (P. aeruginosa).

        '
      action: ACCEPT
      reason: 'Core function - nsy-1 was identified in a screen for susceptibility
        to P. aeruginosa (PMID:12142542). This duplicates another annotation with
        the same term from PMID:17888400.

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: A genetic screen for Caenorhabditis elegans mutants 
            with enhanced susceptibility to killing by Pseudomonas aeruginosa 
            led to the identification of two genes required for pathogen 
            resistance
  - term:
      id: GO:0038066
      label: p38MAPK cascade
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation demonstrating nsy-1 functions in the p38 MAPK cascade
        for innate immunity.

        '
      action: ACCEPT
      reason: 'Core function - the study established that nsy-1/sek-1/pmk-1 constitute
        a conserved p38 MAPK cascade for innate immunity (PMID:12142542).

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: RNA interference assays and biochemical analysis 
            established that a p38 ortholog, pmk-1, functions as the downstream 
            MAP kinase required for pathogen defense
  - term:
      id: GO:1901046
      label: positive regulation of egg-laying behavior
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation indicating nsy-1 positively regulates egg-laying behavior.

        '
      action: KEEP_AS_NON_CORE
      reason: 'While nsy-1 mutants show egg-laying defects, this is likely a secondary
        phenotype of disrupted MAPK signaling rather than a primary function. The
        reference (PMID:12142542) focuses on innate immunity, not egg-laying.

        '
      supported_by:
        - reference_id: UniProt:Q21029
          supporting_text: Involved in egg laying
        - reference_id: PMID:12142542
          supporting_text: A conserved p38 MAP kinase pathway in Caenorhabditis 
            elegans innate immunity.
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: IDA
    original_reference_id: PMID:15625192
    review:
      summary: 'IDA annotation showing NSY-1 localizes to postsynaptic density in
        AWC neurons.

        '
      action: ACCEPT
      reason: 'NSY-1 localizes to postsynaptic regions where it co-localizes with
        TIR-1 (PMID:15625192). This localization is important for its role in neuronal
        asymmetry signaling.

        '
      supported_by:
        - reference_id: PMID:15625192
          supporting_text: TIR-1 localizes NSY-1 to post-synaptic regions of 
            AWC, and TIR-1 binds UNC-43, suggesting that it assembles a synaptic
            signaling complex that regulates odorant receptor expression
  - term:
      id: GO:0043025
      label: neuronal cell body
    evidence_type: IDA
    original_reference_id: PMID:15625192
    review:
      summary: 'IDA annotation showing NSY-1 localizes to neuronal cell bodies (perikaryon).

        '
      action: ACCEPT
      reason: 'NSY-1::GFP localization studies showed expression in neuronal cell
        bodies in addition to axons (PMID:15625192).

        '
      supported_by:
        - reference_id: PMID:15625192
          supporting_text: A Toll-interleukin 1 repeat protein at the synapse 
            specifies asymmetric odorant receptor expression via ASK1 MAPKKK 
            signaling.
  - term:
      id: GO:0006935
      label: chemotaxis
    evidence_type: IMP
    original_reference_id: PMID:11287957
    review:
      summary: 'IMP annotation showing nsy-1 affects chemotaxis behavior, specifically
        odor discrimination.

        '
      action: ACCEPT
      reason: 'nsy-1 mutants show defects in odor discrimination and chemotaxis due
        to disrupted AWC asymmetry. The study shows "nsy-1 mutants exhibit discrimination
        and olfactory defects" (PMID:11287957).

        '
      supported_by:
        - reference_id: PMID:11287957
          supporting_text: C. elegans odour discrimination requires asymmetric 
            diversity in olfactory neurons.
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IMP
    original_reference_id: PMID:12142542
    review:
      summary: 'IMP annotation showing nsy-1 is required for innate immune response.

        '
      action: ACCEPT
      reason: 'This is a core function of nsy-1. The gene was identified in a screen
        for innate immunity mutants and is required for defense against pathogens
        (PMID:12142542).

        '
      supported_by:
        - reference_id: PMID:12142542
          supporting_text: These data suggest that this MAP kinase signaling 
            cassette represents an ancient feature of innate immune responses in
            evolutionarily diverse species
  - term:
      id: GO:0045165
      label: cell fate commitment
    evidence_type: IMP
    original_reference_id: PMID:10571181
    review:
      summary: 'IMP annotation indicating nsy-1 is involved in cell fate commitment,
        specifically in AWC neuronal asymmetry.

        '
      action: ACCEPT
      reason: 'NSY-1 is required for the commitment of AWC neurons to asymmetric fates
        (AWC-ON vs AWC-OFF). The pathway determines which neuron expresses str-2 (PMID:10571181,
        PMID:11751572).

        '
      supported_by:
        - reference_id: PMID:11751572
          supporting_text: the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ 
            signaling through CaMKII and establishes asymmetric cell fate 
            decision during neuronal development
        - reference_id: PMID:10571181
          supporting_text: Lateral signaling mediated by axon contact and 
            calcium entry regulates asymmetric odorant receptor expression in C.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10571181
    title: Lateral signaling mediated by axon contact and calcium entry 
      regulates asymmetric odorant receptor expression in C. elegans.
    findings:
      - statement: NSY-1 functions downstream of Ca2+ signaling and CaMKII 
          (UNC-43) in AWC asymmetry
        supporting_text: CaMKII activity acts as a switch in the initial 
          decision to express str-2; thus, calcium signals can define distinct 
          cell types during neuronal development
      - statement: Calcium signals define distinct cell types during neuronal 
          development
        supporting_text: calcium signals can define distinct cell types during 
          neuronal development
  - id: PMID:11287957
    title: C. elegans odour discrimination requires asymmetric diversity in 
      olfactory neurons.
    findings:
      - statement: nsy-1 mutants (including ky542) have STR-2 expressed in both 
          AWC neurons
        supporting_text: ky542 is an allele of nsy-1, a neuronal symmetry, or 
          Nsy, mutant in which STR-2 is expressed in both AWC neurons
      - statement: Nsy mutants exhibit chemotaxis and odor discrimination 
          defects
        supporting_text: Other Nsy mutants exhibit discrimination and olfactory 
          defects like those of nsy-1 mutants
  - id: PMID:11336672
    title: The CaMKII UNC-43 activates the MAPKKK NSY-1 to execute a lateral 
      signaling decision required for asymmetric olfactory neuron fates.
    findings:
      - statement: NSY-1 kinase activity demonstrated biochemically
        supporting_text: nsy-1 encodes a homolog of the human MAP kinase kinase 
          kinase (MAPKKK) ASK1, an activator of JNK and p38 kinases
      - statement: UNC-43/CaMKII activates NSY-1
        supporting_text: Based on genetic epistasis analysis, nsy-1 appears to 
          act downstream of the CaMKII unc-43, and NSY-1 associates with UNC-43,
          suggesting that UNC-43/CaMKII activates the NSY-1 MAP kinase cassette
  - id: PMID:11751572
    title: SEK-1 MAPKK mediates Ca2+ signaling to determine neuronal asymmetric 
      development in Caenorhabditis elegans.
    findings:
      - statement: NSY-1 is a MAP3K that phosphorylates SEK-1
        supporting_text: Genetic and biochemical analyses reveal that SEK-1 
          functions in a pathway downstream of UNC-43 and NSY-1, 
          Ca2+/calmodulin-dependent protein kinase II (CaMKII) and MAPK kinase 
          kinase (MAPKKK), respectively
      - statement: NSY-1/SEK-1/MAPK cascade activated by Ca2+ signaling
        supporting_text: the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ 
          signaling through CaMKII and establishes asymmetric cell fate decision
          during neuronal development
      - statement: Pathway establishes asymmetric cell fate in AWC neurons
        supporting_text: the NSY-1-SEK-1-MAPK cascade is activated by Ca2+ 
          signaling through CaMKII and establishes asymmetric cell fate decision
          during neuronal development
  - id: PMID:12142542
    title: A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate 
      immunity.
    findings:
      - statement: nsy-1 mutants are susceptible to P. aeruginosa and E. 
          faecalis
        supporting_text: A genetic screen for Caenorhabditis elegans mutants 
          with enhanced susceptibility to killing by Pseudomonas aeruginosa led 
          to the identification of two genes required for pathogen resistance
      - statement: NSY-1/SEK-1/PMK-1 constitute conserved p38 MAPK pathway for 
          innate immunity
        supporting_text: RNA interference assays and biochemical analysis 
          established that a p38 ortholog, pmk-1, functions as the downstream 
          MAP kinase required for pathogen defense
      - statement: Ancient feature of innate immune responses
        supporting_text: These data suggest that this MAP kinase signaling 
          cassette represents an ancient feature of innate immune responses in 
          evolutionarily diverse species
  - id: PMID:15256590
    title: Mitogen-activated protein kinase pathways defend against bacterial 
      pore-forming toxins.
    findings:
      - statement: p38 MAPK pathway defends against Cry5B pore-forming toxin
        supporting_text: A p38 mitogen-activated protein kinase (MAPK) kinase 
          and a c-Jun N-terminal-like MAPK are both transcriptionally 
          up-regulated by Cry5B
      - statement: MAPK pathways are functionally important for toxin defense
        supporting_text: Moreover, both MAPK pathways are functionally important
          because elimination of either leads to animals that are (i) 
          hypersensitive to a low, chronic dose of toxin and (ii) hypersensitive
          to a high, brief dose of toxin such that the animal might naturally 
          encounter in the wild
  - id: PMID:15625192
    title: A Toll-interleukin 1 repeat protein at the synapse specifies 
      asymmetric odorant receptor expression via ASK1 MAPKKK signaling.
    findings:
      - statement: TIR-1 localizes NSY-1 to postsynaptic regions
        supporting_text: TIR-1 localizes NSY-1 to post-synaptic regions of AWC, 
          and TIR-1 binds UNC-43, suggesting that it assembles a synaptic 
          signaling complex that regulates odorant receptor expression
      - statement: TIR-1 acts upstream of NSY-1 in asymmetry pathway
        supporting_text: Genetic evidence suggests that tir-1 acts downstream of
          a voltage-gated calcium channel and CaMKII (UNC-43) to regulate AWC 
          asymmetry via the NSY-1(ASK1) p38/JNK MAP (mitogen-activated protein) 
          kinase cascade
  - id: PMID:17526726
    title: Specificity and complexity of the Caenorhabditis elegans innate 
      immune response.
    findings: []
  - id: PMID:17888400
    title: Caenorhabditis elegans pgp-5 is involved in resistance to bacterial 
      infection and heavy metal and its regulation requires TIR-1 and a p38 map 
      kinase cascade.
    findings: []
  - id: PMID:22308034
    title: Stabilization of RNT-1 protein, runt-related transcription factor 
      (RUNX) protein homolog of Caenorhabditis elegans, by oxidative stress 
      through mitogen-activated protein kinase pathway.
    findings: []
  - id: PMID:22470487
    title: The pseudokinase NIPI-4 is a novel regulator of antimicrobial peptide
      gene expression.
    findings:
      - statement: NSY-1 is part of MAPK cassette for antimicrobial peptide 
          induction
        supporting_text: "We have shown that for nlp-29 cluster genes, following both
          infection and injury, inductive signaling passes via TPA-1, a protein kinase
          C delta (PKC∂) that acts upstream of TIR-1, the nematode ortholog of SARM,
          and a MAPK cassette comprising the MAP3K NSY-1, the MAP2K SEK-1, and PMK-1
          [20]"
      - statement: Required for nlp-29 induction after D. coniospora infection
        supporting_text: We undertook a large-scale genetic screen for mutants 
          that prevented the normal induction of a Pnlp-29::GFP reporter 
          transgene after infection with D. coniospora
  - id: PMID:23352664
    title: A fasting-responsive signaling pathway that extends life span in C. 
      elegans.
    findings: []
  - id: file:worm/nsy-1/nsy-1-deep-research-falcon.md
    title: Deep research report on nsy-1
    findings: []
core_functions:
  - description: 'NSY-1 is a MAP3K (MAP kinase kinase kinase) that phosphorylates
      and activates SEK-1 (MAPKK), which in turn activates PMK-1 (p38 MAPK). This
      is the core molecular function, with EC 2.7.11.25.

      '
    molecular_function:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    directly_involved_in:
      - id: GO:0038066
        label: p38MAPK cascade
  - description: 'NSY-1 functions at the apex of the conserved p38 MAPK cascade (NSY-1/SEK-1/PMK-1)
      that determines left/right asymmetric odorant receptor (str-2) expression in
      AWC neurons. Acts downstream of TIR-1 and UNC-43/CaMKII.

      '
    molecular_function:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    directly_involved_in:
      - id: GO:0035545
        label: determination of left/right asymmetry in nervous system
    locations:
      - id: GO:0014069
        label: postsynaptic density
  - description: 'NSY-1 is essential for defense against bacterial pathogens including
      both Gram-positive (E. faecalis) and Gram-negative (P. aeruginosa) bacteria
      through the p38 MAPK pathway.

      '
    molecular_function:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    directly_involved_in:
      - id: GO:0140367
        label: antibacterial innate immune response
      - id: GO:0050829
        label: defense response to Gram-negative bacterium
      - id: GO:0050830
        label: defense response to Gram-positive bacterium
  - description: 'NSY-1 is required for the innate immune response to fungal pathogens
      such as Drechmeria coniospora, regulating antimicrobial peptide gene expression.

      '
    molecular_function:
      id: GO:0004709
      label: MAP kinase kinase kinase activity
    directly_involved_in:
      - id: GO:0050832
        label: defense response to fungus
tags:
  - caeel-surveillance-immunity

nsy-1

Gene Description

Existing Annotations Review

Core Functions

NSY-1 is a MAP3K (MAP kinase kinase kinase) that phosphorylates and activates SEK-1 (MAPKK), which in turn activates PMK-1 (p38 MAPK). This is the core molecular function, with EC 2.7.11.25.

NSY-1 functions at the apex of the conserved p38 MAPK cascade (NSY-1/SEK-1/PMK-1) that determines left/right asymmetric odorant receptor (str-2) expression in AWC neurons. Acts downstream of TIR-1 and UNC-43/CaMKII.

NSY-1 is essential for defense against bacterial pathogens including both Gram-positive (E. faecalis) and Gram-negative (P. aeruginosa) bacteria through the p38 MAPK pathway.

NSY-1 is required for the innate immune response to fungal pathogens such as Drechmeria coniospora, regulating antimicrobial peptide gene expression.

References

Tags

📚 Additional Documentation

Deep Research Falcon

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Gene Research for Functional Annotation

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Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

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