NPHP-1 is the C. elegans ortholog of human nephrocystin-1 (NPHP1), a protein mutated in nephronophthisis. It localizes specifically to the ciliary transition zone (TZ) in sensory neurons and functions as part of the NPHP module that works redundantly with the MKS module to establish the ciliary gate. NPHP-1 plays important roles in ciliary structure, sensory signal transduction, and male mating behaviors. The protein contains an SH3 domain and requires NPHP-4 for proper TZ localization. Together with NPHP-4, it regulates ciliary access of IFT machinery components, axonemal structural proteins, and signaling molecules.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation based on phylogenetic analysis. While NPHP-1 is predominantly localized to the ciliary transition zone, cytoplasmic localization is plausible as the protein must transit through the cytoplasm. However, this is a generic term that does not capture the protein's specific and functionally relevant localization at the transition zone. Reason: The annotation is not incorrect but does not represent the core localization of NPHP-1. The protein's critical function is at the transition zone. Cytoplasmic localization may represent transit or a minor pool, but the more informative and functionally relevant localizations are the TZ-related terms. Supporting Evidence: file:worm/nphp-1/nphp-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic analysis. NPHP-1 localizes to the ciliary transition zone, which is a subdomain of the cilium. Multiple studies demonstrate TZ-specific localization in C. elegans [PMID:15817158, PMID:18316409, PMID:21422230]. Reason: While the more specific term 'ciliary transition zone' (GO:0035869) better captures NPHP-1's localization, this broader term is accurate since the TZ is part of the cilium. The IBA annotation aligns with experimental evidence showing ciliary localization. Supporting Evidence: PMID:15817158 GFP-tagged NPHP-1 and NPHP-4 proteins localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia. PMID:18316409 GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization |
| GO:0090251 protein localization involved in establishment of planar polarity | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA annotation based on phylogenetic inference. This annotation likely derives from mammalian data where NPHP1 has been implicated in planar cell polarity pathways. There is no direct evidence for this function in C. elegans. Reason: While this may be a conserved function based on phylogenetic analysis, there is no direct experimental evidence for a role in planar polarity in C. elegans. The IBA annotation is reasonable given conservation, but without C. elegans-specific data, this remains speculative. |
| GO:0030030 cell projection organization | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping (cilium biogenesis/degradation). NPHP-1 is involved in cilium structure and organization, particularly through its role at the transition zone. Reason: The annotation is supported by experimental evidence showing that nphp-1 mutants have defects in CEM cilia morphology [PMID:18316409]. NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary structure, and loss causes cell type-specific phenotypes in cilia organization. Supporting Evidence: PMID:18316409 nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum |
| GO:0036064 ciliary basal body | IDA PMID:27623382 A Conserved Role for Girdin in Basal Body Positioning and Ci... | MODIFY | Summary: IDA annotation from a study on Girdin's role in basal body positioning. The paper examines various ciliary proteins including NPHP-1 localization. However, multiple C. elegans studies show NPHP-1 specifically localizes to the transition zone rather than the basal body proper [PMID:18316409, PMID:21422230]. Reason: In C. elegans, the basal body and transition zone are distinct regions. Multiple detailed studies using GFP-tagged NPHP-1 show specific localization to the transition zone, not the basal body. The transition zone is adjacent to but distinct from the basal body region where IFT proteins concentrate. This annotation should be modified to reflect TZ localization. Proposed replacements: ciliary transition zone Supporting Evidence: PMID:18316409 GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization PMID:21422230 we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB) |
| GO:0035869 ciliary transition zone | IDA PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | ACCEPT | Summary: Direct experimental evidence from a study on TMEM107 and ciliopathy proteins. NPHP-1 TZ localization is well-established across multiple C. elegans studies. Reason: This is the core localization for NPHP-1. Multiple studies demonstrate specific TZ localization using fluorescently tagged proteins [PMID:15817158, PMID:18316409, PMID:21422230, PMID:26595381]. NPHP-1 is part of the NPHP module that localizes to and functions at the transition zone. Supporting Evidence: PMID:26595381 nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins PMID:21422230 NPHP-1 and NPHP-4 localize to the TZ in mks-5 mutants, but to a subregion smaller than that occupied in N2 |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: ND (No biological Data) annotation indicating no molecular function is annotated. This is a placeholder annotation used when no experimental data defines a specific molecular function. Reason: Despite extensive characterization of NPHP-1's cellular role, no specific molecular function (e.g., enzyme activity, specific binding activity) has been experimentally determined. The protein contains an SH3 domain which suggests protein-protein interaction capability, but no specific molecular function has been annotated with experimental evidence. The ND annotation is appropriate. |
| GO:0097546 ciliary base | IDA PMID:25335890 Ciliopathy proteins establish a bipartite signaling compartm... | ACCEPT | Summary: IDA annotation from a study on ciliopathy proteins in AFD thermosensory neurons. The study examines how ciliary proteins establish signaling compartments. Reason: The ciliary base encompasses the transition zone and basal body region. NPHP-1 localization to this region is well-documented. This broader term is accurate as an annotation alongside the more specific TZ term. Supporting Evidence: PMID:25335890 proteins associated with Bardet-Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base |
| GO:0023041 neuronal signal transduction | IC PMID:15817158 Functional characterization of the C. elegans nephrocystins ... | ACCEPT | Summary: IC (Inferred by Curator) annotation inferring a role in neuronal signal transduction based on localization to non-motile cilia in sensory neurons and mating behavior phenotypes. Reason: NPHP-1 localizes to sensory cilia in neurons and contributes to sensory behaviors. The double mutant nphp-1;nphp-4 shows response defects, supporting a role in sensory signal transduction. The IC inference from localization and behavioral phenotypes is reasonable. Supporting Evidence: PMID:15817158 We propose that NPHP-1 and NPHP-4 proteins play important and redundant roles in facilitating ciliary sensory signal transduction. |
| GO:0034606 response to hermaphrodite contact | IGI PMID:15817158 Functional characterization of the C. elegans nephrocystins ... | ACCEPT | Summary: IGI (Inferred from Genetic Interaction) annotation based on interaction with nphp-4. Double mutant nphp-1;nphp-4 males show defects in response behaviors during mating. Reason: The annotation captures the redundant role of NPHP-1 and NPHP-4 in male mating behaviors. While single mutants have mild phenotypes, the double mutant shows clear behavioral defects. Supporting Evidence: PMID:15817158 nphp-1; nphp-4 double, but not single, mutant males are response defective. |
| GO:0034607 turning behavior involved in mating | IGI PMID:15817158 Functional characterization of the C. elegans nephrocystins ... | KEEP AS NON CORE | Summary: Turning-behaviour defects seen in nphp-1;nphp-4 double mutants are downstream of impaired ciliary signalling in male-specific sensory neurons, not a direct molecular function of NPHP-1. Reason: Ciliary gene; the mating-turning behaviour is a distal phenotypic consequence of cilium dysfunction; non-core per the behaviour-annotation rubric. Supporting Evidence: PMID:15817158 nphp-1; nphp-4 double, but not single, mutant males are response defective. |
| GO:0097730 non-motile cilium | IDA PMID:15817158 Functional characterization of the C. elegans nephrocystins ... | ACCEPT | Summary: IDA annotation showing NPHP-1 localizes to non-motile (primary/sensory) cilia. C. elegans sensory neurons have non-motile cilia, and NPHP-1 localizes to these structures. Reason: All C. elegans sensory cilia are non-motile (9+0 configuration), and NPHP-1 is expressed in and localizes to ciliated sensory neurons. This is a correct and well-supported annotation. Supporting Evidence: PMID:15817158 GFP-tagged NPHP-1 and NPHP-4 proteins localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia. |
| GO:0035869 ciliary transition zone | IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans... | ACCEPT | Summary: IDA annotation from the comprehensive study on MKS and NPHP modules at the transition zone. This paper provides detailed characterization of NPHP-1 TZ localization and function. Reason: This is a core localization for NPHP-1 supported by extensive experimental evidence. The study uses fluorophore-tagged proteins and demonstrates NPHP-1 specifically localizes to the TZ region. Duplicate with PMID:26595381 annotation but from different reference. Supporting Evidence: PMID:21422230 Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB). |
| GO:0008340 determination of adult lifespan | IMP PMID:19208769 Functional interactions between the ciliopathy-associated Me... | KEEP AS NON CORE | Summary: IMP annotation based on lifespan phenotype in double mutants. The study on MKS1-related proteins found that mks/mksr double mutants with nphp mutations show increased lifespan due to abnormal insulin-IGF-I signaling. Reason: This is a pleiotropic phenotype likely resulting from disrupted ciliary function affecting sensory signaling pathways that regulate lifespan (insulin/IGF-1 signaling). Not a core function of NPHP-1 but rather a consequence of ciliary/sensory dysfunction. Supporting Evidence: PMID:19208769 we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling |
| GO:0008104 intracellular protein localization | IGI PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif... | MODIFY | Summary: IGI annotation indicating NPHP-1 participates in regulating protein localization within the cell, specifically at the ciliary transition zone. Reason: This annotation is too general. NPHP-1 specifically functions at the TZ to regulate ciliary access of IFT components and other proteins. A more specific term related to ciliary protein localization or ciliary gate function would be more appropriate. Proposed replacements: intraciliary transport involved in cilium assembly Supporting Evidence: PMID:18316409 In conclusion, loss of both NPHP-1 and NPHP-4 but not NPHP-1 alone leads to the abnormal ciliary localization of the IFT-B polypeptide OSM-6, the OSM-3-kinesin, and the BBS proteins BBS-7 and BBS-8. PMID:21422230 the two modules restrict inappropriate accumulation of membrane-associated proteins inside cilia |
| GO:0097730 non-motile cilium | IDA PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif... | ACCEPT | Summary: IDA annotation confirming localization to non-motile cilia based on comprehensive characterization of nephrocystin function in C. elegans. Reason: Duplicate of annotation from PMID:15817158 but from different reference. Both support NPHP-1 localization to non-motile sensory cilia. Valid annotation. Supporting Evidence: PMID:18316409 C. elegans nphp-1 and nphp-4 orthologues are expressed in the ciliated sensory nervous system |
| GO:1905515 non-motile cilium assembly | IMP PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif... | ACCEPT | Summary: IMP annotation based on ciliary assembly defects observed in nephrocystin mutants. The study shows NPHP-1 and NPHP-4 are important for proper cilium assembly and structure. Reason: UniProt states NPHP-1 may be necessary for initial assembly of the cilium. The Jauregui 2008 study demonstrates that NPHP-1 and NPHP-4 act at the TZ to regulate ciliary components, and double mutants have ciliary structure defects. NPHP-1 contributes to cilium assembly through its role at the TZ. Supporting Evidence: PMID:18316409 nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum PMID:21422230 MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension |
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Download this section (compressed HTML)Q: What is the precise molecular function of the SH3 domain in NPHP-1?
Q: Does NPHP-1 directly participate in Y-link formation at the transition zone?
Q: Are there specific protein-protein interactions mediated by NPHP-1 that are essential for ciliary gate function?
Experiment: Identify direct binding partners of NPHP-1 using immunoprecipitation or proximity labeling approaches
Hypothesis: NPHP-1 interacts with specific TZ proteins through its SH3 domain
Experiment: Determine if the SH3 domain is required for TZ localization using domain deletion constructs
Hypothesis: The SH3 domain mediates protein-protein interactions required for TZ anchoring
Experiment: Examine whether NPHP-1 is a structural component of Y-links using immuno-EM
Hypothesis: NPHP-1 may be a direct structural component of Y-link connectors
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