TIR-1 is the C. elegans ortholog of mammalian SARM1 (Sterile Alpha and TIR Motif-containing protein 1). It functions as an NAD+ hydrolase (NADase) that cleaves NAD+ to produce ADP-ribose and nicotinamide. TIR-1 plays dual roles in the nematode: (1) as a central component of TLR-independent innate immunity, acting upstream of the NSY-1/SEK-1/PMK-1 p38 MAPK signaling cascade to regulate antimicrobial peptide gene expression in response to bacterial and fungal pathogens; and (2) in neuronal development, specifically in the specification of asymmetric AWC olfactory neuron identity through its signaling adaptor function and localization to postsynaptic regions via its SAM domains. The TIR domain mediates the NADase enzymatic activity while the SAM domains mediate oligomerization and synaptic localization. TIR-1 also regulates serotonin biosynthesis in ADF chemosensory neurons in response to pathogenic food and participates in axon degeneration pathways. The protein homodimerizes and interacts with UNC-43/CaMKII, NSY-1/ASK1, and small GTPases like RAB-1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030425 dendrite | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference from PANTHER. The mammalian ortholog SARM1 is localized to dendrites. In C. elegans, TIR-1 has been shown to localize to postsynaptic regions of axons in AWC neurons (PMID:15625192), though dendrite localization has not been directly demonstrated. Given the conserved function and the evidence for synaptic localization, this is a reasonable inference. Reason: Phylogenetic inference is reasonable given the conservation of SARM1 function. While direct evidence in C. elegans shows axon/postsynaptic localization, the IBA annotation from PANTHER reflects likely conserved subcellular distribution patterns. 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 file:worm/tir-1/tir-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0002376 immune system process | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation based on UniProt keyword mapping. TIR-1 is well-established as a central player in C. elegans innate immunity, acting upstream of the p38 MAPK cascade to regulate antimicrobial gene expression. Reason: While the annotation is correct, it is too general. More specific annotations for innate immune response and defense responses to pathogens are already present with experimental evidence. This IEA provides no additional information beyond what is captured by more specific terms. Proposed replacements: innate immune response Supporting Evidence: PMID:15048112 tir-1, which encodes an ortholog of SARM, a Toll-interleukin 1 receptor (TIR) domain protein |
| GO:0003953 NAD+ nucleosidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from InterPro domain mapping. This is strongly supported by direct experimental evidence showing TIR-1 has NAD+ hydrolase activity, cleaving NAD+ to ADP-ribose and nicotinamide (PMID:31439792, PMID:34184985). Reason: Correct annotation supported by multiple IDA evidence from experimental publications. The IEA annotation is consistent with direct experimental evidence. Supporting Evidence: PMID:31439792 feature self-association-dependent NAD+ cleavage activity associated with cell death signaling |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location vocabulary mapping. This is supported by direct experimental evidence (PMID:15625192). Reason: Consistent with IDA evidence from PMID:15625192 showing cytoplasmic localization. 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:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro TIR domain mapping. TIR-1 functions as a signaling adaptor upstream of the NSY-1/SEK-1/PMK-1 p38 MAPK cascade in both immune and neuronal signaling. Reason: Correct but general annotation. TIR-1 clearly functions in signal transduction as an adaptor protein activating MAPK cascades. Supporting Evidence: PMID:15625192 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 |
| GO:0007399 nervous system development | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IEA annotation from UniProt keyword mapping. TIR-1 is involved in AWC olfactory neuron asymmetric development, specifying AWC(OFF) identity through the NSY-1/PMK-1 MAPK cascade. Reason: While TIR-1 does play a role in AWC neuron specification, this is a specific developmental function rather than general nervous system development. The primary conserved function is NADase activity and immune signaling. The neuronal role is an important but secondary function. Supporting Evidence: PMID:15625192 encodes a conserved post-synaptic protein that specifies the choice between AWC(OFF) and AWC(ON) |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping. TIR-1 has NAD+ hydrolase activity. Reason: Correct but very general. The more specific NAD+ nucleosidase activity term is also annotated. This parent term is acceptable as additional annotation. Supporting Evidence: PMID:31439792 feature self-association-dependent NAD+ cleavage activity associated with cell death signaling |
| GO:0019677 NAD+ catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA machine learning. TIR-1 catalyzes NAD+ hydrolysis, depleting cellular NAD+ pools. Reason: Correct annotation supported by multiple IDA experimental evidence from PMID:27671644, PMID:31439792, and PMID:34184985. Supporting Evidence: PMID:27671644 dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD+ and induces neuronal destruction |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IEA annotation from UniProt keyword mapping. TIR-1 is involved in AWC neuron asymmetric specification, which is a form of cell differentiation. Reason: Too general. The specific role is in AWC neuron fate specification (GO:0001708), which is already annotated with experimental evidence. This general term does not add much information. Supporting Evidence: PMID:15625192 encodes a conserved post-synaptic protein that specifies the choice between AWC(OFF) and AWC(ON) |
| GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway | IEA GO_REF:0000002 | REMOVE | Summary: IEA annotation from InterPro SARM1 family mapping. Mammalian SARM1 negatively regulates TLR signaling, but this function has not been demonstrated for C. elegans TIR-1. In fact, C. elegans TIR-1 acts independently of the sole Toll receptor TOL-1. Reason: This annotation is based on mammalian SARM1 function but may not apply to C. elegans TIR-1. The nematode TIR-1 functions in a TLR-independent manner. PMID:15048112 explicitly states TIR-1 activity is independent of the single nematode Toll-like receptor. Supporting Evidence: PMID:15048112 the activity of tir-1 was independent of the single nematode Toll-like receptor |
| GO:0035591 signaling adaptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro. TIR-1 functions as a signaling adaptor, assembling signaling complexes at synapses that regulate downstream MAPK cascades. Reason: Correct annotation also supported by IDA evidence from PMID:15625192. Supporting Evidence: PMID:15625192 TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression |
| GO:0044297 cell body | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA. TIR-1 localizes to neuronal cell bodies in addition to axons. Reason: Consistent with IDA evidence from PMID:23505381 showing localization to cell bodies and axons. Supporting Evidence: PMID:23505381 Regulation of TIR-1 signaling in ADF neurons |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping. TIR-1 is a key regulator of innate immunity in C. elegans. Reason: Core function of TIR-1 well-supported by experimental evidence. Supporting Evidence: PMID:15048112 tir-1, which encodes an ortholog of SARM, a Toll-interleukin 1 receptor (TIR) domain protein |
| GO:0048678 response to axon injury | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined methods. TIR-1/SARM1 is an evolutionarily conserved executioner of axon degeneration (Wallerian degeneration). Reason: Core conserved function of SARM1 family, supported by IDA and IMP evidence from PMID:27671644 and PMID:34184985. Supporting Evidence: PMID:27671644 Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration |
| GO:0061809 NAD+ nucleosidase activity, cyclic ADP-ribose generating | IEA GO_REF:0000003 | UNDECIDED | Summary: IEA annotation from EC number mapping (EC:3.2.2.6). TIR-1/SARM1 cleaves NAD+ to produce ADP-ribose and nicotinamide, but whether it produces cyclic ADP-ribose is unclear. Reason: The EC number 3.2.2.6 covers NAD+ nucleosidase activity which can produce cyclic ADP-ribose. However, the primary product of SARM1/TIR-1 is linear ADP-ribose, not cyclic ADP-ribose. PMID:31439792 describes cleavage without mentioning cyclic products. More specific evidence is needed. Supporting Evidence: PMID:31439792 feature self-association-dependent NAD+ cleavage activity associated with cell death signaling |
| GO:0042802 identical protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | ACCEPT | Summary: IPI annotation from high-throughput yeast two-hybrid screen showing TIR-1 self-interaction. TIR-1/SARM1 homodimerization is essential for its NADase activity. Reason: TIR-1 homodimerization is well-established and functionally important. UniProt states TIR-1 is a homodimer (PMID:15048112, PMID:27671644). Supporting Evidence: PMID:27671644 Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD+ loss and neuronal death |
| GO:0042802 identical protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | ACCEPT | Summary: Second IPI annotation from empirically controlled C. elegans interactome mapping confirming TIR-1 self-interaction. Reason: Independent confirmation of TIR-1 homodimerization from high-quality interactome study. Supporting Evidence: PMID:19123269 Through a new empirical quality control framework, we show that the resulting data set (Worm Interactome 2007, or WI-2007) was similar in quality to low-throughput data curated from the literature |
| GO:0001708 cell fate specification | IMP PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | KEEP AS NON CORE | Summary: IMP annotation based on tir-1 mutant phenotype showing loss of AWC(OFF) vs AWC(ON) asymmetry. TIR-1 is required for specifying AWC olfactory neuron asymmetric identity. Reason: This is a well-supported but non-core function of TIR-1. The primary conserved functions are NADase activity and immune signaling. The AWC specification role is specific to C. elegans neurodevelopment. Supporting Evidence: PMID:15625192 encodes a conserved post-synaptic protein that specifies the choice between AWC(OFF) and AWC(ON) |
| GO:0007267 cell-cell signaling | IMP PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | KEEP AS NON CORE | Summary: IMP annotation based on tir-1's role in lateral signaling between AWC neurons. Reason: TIR-1 participates in stochastic lateral signaling between AWC neurons during development. This is a specific developmental role, not a core function. Supporting Evidence: PMID:15625192 A stochastic lateral signaling interaction between two developing Caenorhabditis elegans AWC olfactory neurons causes them to take on asymmetric patterns of odorant receptor expression |
| 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 based on tir-1 requirement for resistance to Pseudomonas aeruginosa infection and regulation of pgp-5 expression in response to bacterial infection. Reason: Core immune function of TIR-1 in defense against Gram-negative bacteria like P. aeruginosa. Supporting Evidence: PMID:17888400 signals from both biotic and abiotic stresses are integrated by TIR-1, a TIR domain adaptor protein orthologous to human SARM, and a p38 MAP kinase signaling cassette |
| GO:0048678 response to axon injury | IDA PMID:27671644 SARM1-specific motifs in the TIR domain enable NAD+ loss and... | ACCEPT | Summary: IDA annotation showing TIR-1 function in axon degeneration response to injury. Dimerization of TIR domain promotes NAD+ loss and neuronal destruction. Reason: Core conserved function of the SARM1 family in regulating axon degeneration. Supporting Evidence: PMID:27671644 Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD+ loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function |
| GO:0003953 NAD+ nucleosidase activity | IDA PMID:34184985 A phase transition enhances the catalytic activity of SARM1,... | ACCEPT | Summary: IDA annotation demonstrating TIR-1 NAD+ glycohydrolase activity. Phase transition enhances TIR-1/SARM1 catalytic activity. Reason: Direct experimental evidence for core enzymatic function. Supporting Evidence: PMID:34184985 Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to stress |
| GO:0019677 NAD+ catabolic process | IDA PMID:34184985 A phase transition enhances the catalytic activity of SARM1,... | ACCEPT | Summary: IDA annotation showing TIR-1 involvement in NAD+ depletion. Citrate-induced phase transition enhances SARM1/TIR-1 activity leading to NAD+ catabolism. Reason: Core enzymatic function directly demonstrated. Supporting Evidence: PMID:34184985 TIR-1/SARM1 multimerization is essential for degeneration in vivo |
| GO:0048678 response to axon injury | IMP PMID:34184985 A phase transition enhances the catalytic activity of SARM1,... | ACCEPT | Summary: IMP annotation showing TIR-1 requirement for citrate-induced axonal degeneration in C. elegans. Reason: Core conserved function of SARM1/TIR-1 in axon degeneration. Supporting Evidence: PMID:34184985 citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (TIR-1) |
| GO:0140367 antibacterial innate immune response | IMP PMID:19837372 Tissue-specific activities of an immune signaling module reg... | ACCEPT | Summary: IMP annotation showing TIR-1 role in antibacterial immune response through the SARM-ASK1-MKK3 signaling module. Reason: Core immune function of TIR-1. Well-supported by multiple studies. Supporting Evidence: PMID:19837372 Immunity in C. elegans requires a signaling module comprised of orthologs of the mammalian Toll-interleukin-1 receptor (TIR) domain protein SARM, the mitogen-activated protein kinase kinase kinase (MAPKKK) ASK1, and MAPKK MKK3, which activates p38 MAPK |
| GO:0030424 axon | IDA PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | ACCEPT | Summary: IDA annotation showing TIR-1 localization to axons in neurons. Reason: Direct experimental evidence for axonal localization consistent with TIR-1's role at postsynaptic regions. Supporting Evidence: PMID:15625192 TIR-1 is a multidomain protein with a TIR (Toll-interleukin-1 receptor) domain that activates signaling, SAM repeats that mediate localization to post-synaptic regions of axons, and an N-terminal inhibitory domain |
| GO:0044297 cell body | IDA PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | ACCEPT | Summary: IDA annotation showing TIR-1 localization to neuronal cell bodies. Reason: Direct experimental evidence for cell body localization. Supporting Evidence: PMID:23505381 Regulation of TIR-1 signaling in ADF neurons |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | ACCEPT | Summary: IMP annotation showing TIR-1 role in defense against P. aeruginosa through regulation of innate immune and serotonergic responses. Reason: Core immune function. TIR-1 regulates both innate immunity and serotonin biosynthesis in response to pathogenic bacteria. Supporting Evidence: PMID:23505381 A subsequent study indicated that the TIR-domain adaptor protein TIR-1, which was initially identified as an upstream regulator of a conserved mitogen-activated protein kinase (MAPK) signaling pathway in the innate immunity |
| GO:0042427 serotonin biosynthetic process | IMP PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | KEEP AS NON CORE | Summary: IMP annotation showing TIR-1 regulates tph-1 expression in ADF chemosensory neurons, thereby regulating serotonin biosynthesis in response to pathogenic food. Reason: TIR-1 acts upstream of serotonin biosynthesis by regulating tph-1 (tryptophan hydroxylase) expression. This is an indirect effect through transcriptional regulation rather than direct participation in the biosynthetic pathway. The qualifier "acts_upstream_of_or_within" is appropriate. Supporting Evidence: PMID:23505381 feeding worms with the human opportunistic pathogen Pseudomonas aeruginosa PA14 triggers upregulation of tph-1 in the ADF neurons |
| GO:0003953 NAD+ nucleosidase activity | IDA PMID:31439792 NAD(+) cleavage activity by animal and plant TIR domains in ... | ACCEPT | Summary: IDA annotation demonstrating TIR-1 NAD+ cleavage activity. Crystal structures reveal conserved substrate binding site. Reason: Core enzymatic function of TIR-1/SARM1 directly demonstrated biochemically. Supporting Evidence: PMID:31439792 Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD+ cleavage activity associated with cell death signaling |
| GO:0019677 NAD+ catabolic process | IDA PMID:27671644 SARM1-specific motifs in the TIR domain enable NAD+ loss and... | ACCEPT | Summary: IDA annotation showing TIR-1 TIR domain promotes NAD+ consumption when dimerized. Reason: Core enzymatic function directly demonstrated. Supporting Evidence: PMID:27671644 dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD+ and induces neuronal destruction |
| GO:0019677 NAD+ catabolic process | IDA PMID:31439792 NAD(+) cleavage activity by animal and plant TIR domains in ... | ACCEPT | Summary: IDA annotation showing TIR-1 catalyzes NAD+ cleavage to ADP-ribose and nicotinamide. Reason: Core enzymatic function directly demonstrated with structural data. Supporting Evidence: PMID:31439792 feature self-association-dependent NAD+ cleavage activity associated with cell death signaling |
| 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 TIR-1 is required for transcriptional induction of pgp-5 and antimicrobial genes in response to infection. Reason: TIR-1 acts as a signaling adaptor that activates the p38 MAPK cascade, which ultimately leads to transcriptional activation of defense genes. Supporting Evidence: PMID:17888400 the transcription of a Caenorhabditis elegans ABC transporter, pgp-5 is induced by both bacterial infection and heavy metal stress |
| GO:0035591 signaling adaptor activity | IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | ACCEPT | Summary: IDA annotation showing TIR-1 functions as a signaling adaptor that assembles a signaling complex with UNC-43/CaMKII and NSY-1/ASK1 at postsynaptic regions. Reason: Core molecular function of TIR-1, directly demonstrated through interaction studies and localization experiments. 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:0005737 cytoplasm | IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | ACCEPT | Summary: IDA annotation showing cytoplasmic localization of TIR-1. Reason: Direct experimental evidence for cytoplasmic localization in neurons. 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 TIR-1 positively regulates expression of certain antimicrobial genes during innate immune response. Reason: TIR-1 activates the p38 MAPK cascade which leads to transcriptional activation of antimicrobial genes. Supporting Evidence: PMID:17526726 different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes |
| GO:0010629 negative regulation of gene expression | IMP PMID:17526726 Specificity and complexity of the Caenorhabditis elegans inn... | ACCEPT | Summary: IMP annotation showing TIR-1 also negatively regulates expression of some genes during immune response. Reason: The TIR-1/NSY-1/PMK-1 pathway regulates both positive and negative transcriptional responses to pathogens, indicating complex gene regulatory networks. Supporting Evidence: PMID:17526726 different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes |
| GO:1904115 axon cytoplasm | IDA PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | ACCEPT | Summary: IDA annotation showing TIR-1 localizes to cytoplasm of axons, specifically at postsynaptic regions. Reason: Direct experimental evidence showing TIR-1 localization to axonal postsynaptic regions, consistent with its role in neuronal signaling. Supporting Evidence: PMID:15625192 TIR-1 is a multidomain protein with a TIR (Toll-interleukin-1 receptor) domain that activates signaling, SAM repeats that mediate localization to post-synaptic regions of axons, and an N-terminal inhibitory domain |
| GO:0050832 defense response to fungus | IMP PMID:18394898 Distinct innate immune responses to infection and wounding i... | ACCEPT | Summary: IMP annotation showing TIR-1 is required for defense against the fungal pathogen Drechmeria coniospora. TIR-1 regulates nlp-29 expression in epidermis in response to fungal infection. Reason: Core immune function of TIR-1 in defense against fungal pathogens. Supporting Evidence: PMID:18394898 Infection of the nematode Caenorhabditis elegans by the natural fungal pathogen Drechmeria coniospora induces the expression in the epidermis of antimicrobial peptide (AMP) genes such as nlp-29 |
| GO:0050832 defense response to fungus | IMP PMID:15048112 TLR-independent control of innate immunity in Caenorhabditis... | ACCEPT | Summary: IMP annotation from the original TIR-1 innate immunity paper showing requirement for defense against fungal pathogens. Reason: Core immune function of TIR-1, demonstrated in foundational study of its role in innate immunity. Supporting Evidence: PMID:15048112 Inactivation of tir-1 by RNA interference caused increased susceptibility to infection |
| GO:0005515 protein binding | IPI PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | MODIFY | Summary: IPI annotation based on TIR-1 interaction with NSY-1 (WBGene00011273). TIR-1 binds and localizes NSY-1 to postsynaptic regions. Reason: "Protein binding" is uninformative. TIR-1's interaction with NSY-1 is more specifically characterized as signaling adaptor activity. The protein kinase binding annotation (GO:0019901) is more informative. Proposed replacements: protein kinase binding 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:0008104 intracellular protein localization | IMP PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | KEEP AS NON CORE | Summary: IMP annotation showing TIR-1 is required for localization of NSY-1 to postsynaptic regions. The SAM domains of TIR-1 mediate this localization function. Reason: This is a specific developmental/neuronal function rather than a core function. TIR-1 localizes NSY-1 as part of its signaling adaptor function in neurons. 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:0019901 protein kinase binding | IPI PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | ACCEPT | Summary: IPI annotation showing TIR-1 binds NSY-1, the ASK1 MAPKKK ortholog. TIR-1 also interacts with UNC-43/CaMKII. Reason: Well-supported molecular function. TIR-1 binds kinases as part of its signaling adaptor function. Supporting Evidence: PMID:15625192 TIR-1 binds UNC-43, suggesting that it assembles a synaptic signaling complex that regulates odorant receptor expression |
| GO:0031267 small GTPase binding | IPI PMID:15625192 A Toll-interleukin 1 repeat protein at the synapse specifies... | ACCEPT | Summary: IPI annotation showing TIR-1 interacts with RAB-1 small GTPase. RAB-1 participates in control of antimicrobial peptide gene expression. Reason: Directly supported by experimental evidence from the original TIR-1 study. Supporting Evidence: PMID:15048112 We identify protein partners for TIR-1 and show that the small GTPase Rab1 and the f subunit of ATP synthase participate specifically in the control of antimicrobial peptide gene expression |
| GO:0042742 defense response to bacterium | IMP PMID:15048112 TLR-independent control of innate immunity in Caenorhabditis... | ACCEPT | Summary: IMP annotation from the foundational TIR-1 innate immunity paper. TIR-1 RNAi causes increased susceptibility to bacterial infection and reduces antimicrobial peptide gene expression. Reason: Core immune function of TIR-1 well-supported by multiple studies. Supporting Evidence: PMID:15048112 Inactivation of tir-1 by RNA interference caused increased susceptibility to infection |
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Download this section (compressed HTML)Q: Does C. elegans TIR-1 produce cyclic ADP-ribose as a product of NAD+ hydrolysis, or exclusively linear ADP-ribose? The EC:3.2.2.6 annotation suggests cyclic ADP-ribose generating activity, but structural studies show linear ADP-ribose as the primary product.
Q: What is the relative importance of TIR-1's NADase activity versus its signaling adaptor function in innate immune responses? TIR-1 has dual functions but it is unclear if immune signaling depends on NADase activity or scaffolding function or both.
Experiment: Test catalytically dead TIR-1 mutants for immune signaling function to separate NADase activity from adaptor function in immunity. If adaptor function is sufficient, catalytically dead mutants should rescue immune defects. If NADase is required, they should fail to rescue.
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