NPHP4 (nephrocystin-4, nephroretinin) is a large, conserved, soluble protein built from repeated C2-like and immunoglobulin-like domains. It lies at the distal ciliary transition zone close to the membrane and at the basal body, centrosome and epithelial cell-cell junctions. NPHP4 is the central member of the NPHP1-4-8 (NPHP) module: it binds NPHP1 directly and links it to RPGRIP1L. In Chlamydomonas, NPHP4 is an essential part of the transition-zone barrier that controls the membrane and soluble protein composition of the cilium. In C. elegans, NPHP-4 acts redundantly with the MKS module to attach the basal body and transition zone to the membrane and to build the ciliary gate. At junctions, NPHP4 supports timely tight-junction formation and epithelial morphogenesis. Through Inturned and DAAM1 it organizes the subapical actin network of multiciliated cells. It also regulates signaling: it stabilizes JADE1 and moves it to the nucleus to inhibit canonical Wnt signaling, and it controls PYK2-dependent phosphorylation of NPHP1. NPHP4 mutations cause nephronophthisis type 4 and Senior-Loken syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005198 structural molecule activity | NAS PMID:12006559 Nephrocystin-conserved domains involved in targeting to epit... | REMOVE | Summary: A curator statement of structural molecule activity for NPHP4, citing a nephrocystin (NPHP1) domain-analysis paper. Reason: The cited abstract concerns nephrocystin-1 only and concludes that it is a docking protein. It provides no evidence about NPHP4 activity. GO:0005198 is also a generic placeholder. NPHP4 is a structural component of the transition zone in Chlamydomonas, but no specific molecular activity has been defined for it. Supporting Evidence: PMID:12006559 These findings support a functional role for nephrocystin as a docking protein involved in organizing a protein complex to regulate the actin cytoskeleton at sites of epithelial cell-cell adhesion |
| GO:0005515 protein binding | IPI PMID:12244321 The gene mutated in juvenile nephronophthisis type 4 encodes... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. The first report of the NPHP4-NPHP1 interaction, in the NPHP4 gene identification paper. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:15661758 Characterization of the nephrocystin/nephrocystin-4 complex ... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Domain mapping of the NPHP4-NPHP1 interaction. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:15661758 Characterization of the nephrocystin/nephrocystin-4 complex ... | REMOVE | Summary: Reported physical association of NPHP4 with PTK2B/PYK2. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. PYK2 was detected in the NPHP4-containing complex. NPHP4 regulates PYK2-mediated phosphorylation of NPHP1, but no distinct NPHP4 activity is defined. |
| GO:0005515 protein binding | IPI PMID:17558407 Mutations in the gene encoding the basal body protein RPGRIP... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Patient NPHP4 mutations disrupt this interaction. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005515 protein binding | IPI PMID:20664800 Interaction of ciliary disease protein retinitis pigmentosa ... | REMOVE | Summary: Reported physical association of NPHP4 with RPGR. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. RPGR was co-immunoprecipitated with NPHP1 and NPHP4. This places NPHP4 in the photoreceptor connecting-cilium network. |
| GO:0005515 protein binding | IPI PMID:21224891 Evidence for RPGRIP1 gene as risk factor for primary open an... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. This is a glaucoma-association study reporting an RPGRIP1-NPHP4 interaction. It is relevant to the photoreceptor connecting cilium but defines no NPHP4 activity. |
| GO:0005515 protein binding | IPI PMID:21357692 Nephrocystin-4 regulates Pyk2-induced tyrosine phosphorylati... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. NPHP4 controls the NPHP1/PYK2 interaction. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. LAP-tag proteomics defining the NPHP1-4-8 module. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | REMOVE | Summary: Reported physical association of NPHP4 with IQCB1 (NPHP5). Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. IQCB1 belongs to the separate NPHP5-6 module. This is an inter-module network association. |
| GO:0005515 protein binding | IPI PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. LAP-tag proteomics. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005515 protein binding | IPI PMID:22654112 The ciliary protein nephrocystin-4 translocates the canonica... | REMOVE | Summary: Reported physical association of NPHP4 with JADE1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. NPHP4 stabilizes JADE1 and promotes its nuclear translocation. The regulatory consequence is captured by the negative regulation of canonical Wnt signaling annotations. |
| GO:0005515 protein binding | IPI PMID:22863007 Exome capture reveals ZNF423 and CEP164 mutations, linking r... | REMOVE | Summary: Reported physical association of NPHP4 with CEP164. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. CEP164 is a distal-appendage protein. The interaction was reported in a renal ciliopathy exome study, and its functional meaning is not defined. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proximity-labelling (BioID) association. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proximity-labelling (BioID) association. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: Reported physical association of NPHP4 with RPGR. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proximity-labelling (BioID) association. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proximity-labelling (BioID) association. |
| GO:0005515 protein binding | IPI PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to contro... | REMOVE | Summary: Reported physical association of NPHP4 with INTU (Inturned). Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. INTU links NPHP4 to the formin DAAM1 to control subapical actin in multiciliated cells. The process is captured as actin cytoskeleton organization. |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Ciliary affinity proteomics. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Ciliary affinity proteomics. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005515 protein binding | IPI PMID:29959317 Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ... | REMOVE | Summary: Reported physical association of NPHP4 with RUVBL1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. NPHP4 was used as a tagged partner in a study of RUVBL1 and ciliary integrity. |
| GO:0005515 protein binding | IPI PMID:30471718 Recessive DNAH9 Loss-of-Function Mutations Cause Laterality ... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. This interaction was used as a control or context in a DNAH9 laterality paper. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proteome-scale interaction map. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Reported physical association of NPHP4 with RPGR. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Proteome-scale interaction map. |
| GO:0005515 protein binding | IPI PMID:40739040 Multi-proteomic profiling of the varicella-zoster virus-host... | REMOVE | Summary: Reported physical association of NPHP4 with NPHP1. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Virus-host multi-proteomics study. NPHP4 binds NPHP1 directly and links NPHP1 to RPGRIP1L in the NPHP1-4-8 module. This is better represented by the NPHP complex (GO:1990957) annotation. |
| GO:0005515 protein binding | IPI PMID:40739040 Multi-proteomic profiling of the varicella-zoster virus-host... | REMOVE | Summary: Reported physical association of NPHP4 with RPGRIP1L. Reason: GO:0005515 protein binding is uninformative about the molecular activity of NPHP4. The interaction itself is not disputed. Virus-host multi-proteomics study. RPGRIP1L (NPHP8) is the third core member of the NPHP1-4-8 module and the transition-zone assembly hub. Complex membership is captured by GO:1990957. |
| GO:0005634 nucleus | EXP PMID:22654112 The ciliary protein nephrocystin-4 translocates the canonica... | KEEP AS NON CORE | Summary: A nuclear pool of NPHP4 was detected. NPHP4 promotes nuclear translocation of the Wnt regulator JADE1. Reason: The experimental evidence is accepted, but the nucleus is a secondary location. The main functional sites of NPHP4 are the transition zone and cell junctions. Supporting Evidence: PMID:22654112 NPHP4 stabilizes protein levels of Jade-1 and promotes the translocation of Jade-1 to the nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to the nucleus. Reason: This is consistent with the experimental nuclear pool but is not the core location. Supporting Evidence: PMID:22654112 NPHP4 stabilizes protein levels of Jade-1 and promotes the translocation of Jade-1 to the nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: NPHP4 is a soluble cytoplasmic protein that concentrates at the basal body, transition zone and cell junctions. Reason: This is a correct general location. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005813 centrosome | IDA PMID:21399614 Novel asymmetrically localizing components of human centroso... | ACCEPT | Summary: NPHP4 was identified among centrosome components in a human centrosome proteomics and localization study. Reason: The cached abstract does not name NPHP4. The identification is presumably in the full data set, which the curator read. Centrosomal localization of NPHP4 in dividing cells is independently reported (PMID:15661758), so the annotation is accepted. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt mapping of NPHP4 to the centrosome. Reason: This is consistent with the experimental data. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005814 centriole | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based annotation of NPHP4 to the centriole. Reason: NPHP4 sits at the basal body (the mother centriole) and the adjacent transition zone. The term is acceptable but less precise than ciliary basal body or transition zone. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2059926 | KEEP AS NON CORE | Summary: Reactome places NPHP4 in the cytosol for its binding to LATS kinases (Hippo pathway). Reason: NPHP4 is a cytoplasmic protein, and the LATS1 interaction is reported in UniProt. Cytosol is correct but not the core site. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | KEEP AS NON CORE | Summary: Reactome places NPHP4 in the cytosol in the RAB3IP/RAB8A ciliary-vesicle step. Reason: This is a cytosolic pool and is non-core. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | KEEP AS NON CORE | Summary: Reactome places NPHP4 in the cytosol for the 'Recruitment of transition zone proteins' event. Reason: This describes the cytosolic pool before recruitment and is non-core. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | KEEP AS NON CORE | Summary: Reactome places NPHP4 in the cytosol for CEP164-dependent vesicle recruitment. Reason: This is non-core. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005856 cytoskeleton | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation of NPHP4 to the cytoskeleton. Reason: NPHP4 associates with microtubule-based structures (basal body, centrosome and transition zone) and with cortical actin. This is acceptable as a broad parent. Supporting Evidence: PMID:15661758 nephrocystin-4 was also detected at the centrosomes of dividing cells and close to the cortical actin cytoskeleton in polarized cells |
| GO:0005911 cell-cell junction | IDA PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | ACCEPT | Summary: NPHP4 accumulates at cell-cell contacts of polarized renal epithelial cells together with NPHP1 and RPGRIP1L. Reason: This is direct localization evidence. Supporting Evidence: PMID:21565611 as cells approach confluence and develop into polarized epithelial monolayers, these NPHP proteins accumulate to cell-cell contacts, mostly basolateral of tight junctions |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000044 | ACCEPT | Summary: NPHP4 accumulates near basolateral tight junctions (UniProt, by similarity). Reason: This is consistent with human localization at cell-cell contacts and with the tight-junction phenotype. Supporting Evidence: PMID:21565611 as cells approach confluence and develop into polarized epithelial monolayers, these NPHP proteins accumulate to cell-cell contacts, mostly basolateral of tight junctions PMID:19755384 these results indicate that nephrocystins-1 and -4 are required for the proper timing of tight junctional establishment necessary for the formation of a fully polarized epithelial monolayer |
| GO:0007165 signal transduction | NAS PMID:12244321 The gene mutated in juvenile nephronophthisis type 4 encodes... | MARK AS OVER ANNOTATED | Summary: A curator statement, from the NPHP4 identification paper, that NPHP4 and nephrocystin participate in a common signaling pathway. Reason: The paper shows only the NPHP1 interaction and speculates about a signaling pathway. The more specific Wnt-regulatory role is captured separately. Supporting Evidence: PMID:12244321 We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway. |
| GO:0007632 visual behavior | NAS PMID:12205563 A gene mutated in nephronophthisis and retinitis pigmentosa ... | REMOVE | Summary: A curator statement of visual behavior, based on retinitis pigmentosa in Senior-Loken syndrome patients with NPHP4 mutations. Reason: Retinal degeneration reflects photoreceptor connecting-cilium dysfunction. It is not participation in an organism-level visual behavior. Photoreceptor connecting cilium localization already captures the relevant biology. Supporting Evidence: PMID:12205563 Thus, we have identified a novel gene with critical roles in renal tissue architecture and ophthalmic function. |
| GO:0030036 actin cytoskeleton organization | NAS PMID:12006559 Nephrocystin-conserved domains involved in targeting to epit... | KEEP AS NON CORE | Summary: A curator statement of a role in actin cytoskeleton organization. Reason: The cited paper (PMID:12006559) concerns nephrocystin-1 only. However, the process is supported for NPHP4 by later work: NPHP4 recruits Inturned, which links it to the formin DAAM1, and loss of nphp4 disrupts the subapical actin network of multiciliated cells. The annotation is kept as non-core. Supporting Evidence: PMID:26644512 We report now that NPHP4 interacts with Inturned, which facilitated the formation of a tertiary complex between NPHP4 and the actin-nucleating protein Daam1. PMID:26644512 Knockdown of nphp4, inturned, or daam1 in Xenopus resulted in strikingly similar abnormalities of the subapical actin layer. |
| GO:0032391 photoreceptor connecting cilium | IEA GO_REF:0000107 | ACCEPT | Summary: NPHP4 localizes to the photoreceptor connecting cilium. Reason: This is supported by mouse and human data and is consistent with the retinal phenotype. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference that NPHP4 acts at the ciliary transition zone. Reason: This is the core location. NPHP4 is a stable distal transition-zone component in Chlamydomonas and a member of the NPHP module in C. elegans and human. Supporting Evidence: PMID:25150219 NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CEP290, another transition zone protein. PMID:21422230 MKS-5/RPGRIP1L interacts with two distinct TZ functional modules, MKS/MKSR and NPHP, consisting of MKS-1/MKSR-1/MKSR-2/MKS-3/MKS-6 and NPHP-1/NPHP-4 proteins, respectively |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based annotation of NPHP4 to the ciliary transition zone. Reason: This is correct. Supporting Evidence: PMID:25150219 NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CEP290, another transition zone protein. |
| GO:0035869 ciliary transition zone | NAS PMID:28401750 The Ciliary Transition Zone: Finding the Pieces and Assembli... | ACCEPT | Summary: A transition-zone review places NPHP4 in the NPHP module at the transition zone. Reason: This is correct. Supporting Evidence: PMID:25150219 NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CEP290, another transition zone protein. PMID:28401750 However, combining the disruption of a MKS complex component with the disruption of NPHP1 or NPHP4 severely disrupted ciliogenesis, and ciliary functions |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference that NPHP4 acts at the ciliary basal body. Reason: NPHP4 localizes to basal bodies in renal epithelial cells and multiciliated cells. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0036064 ciliary basal body | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based annotation of NPHP4 to the ciliary basal body. Reason: This is correct. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The PAINT inference that NPHP4 negatively regulates canonical Wnt signaling. Reason: NPHP4 stabilizes JADE1 and promotes its nuclear translocation, enhancing JADE1-mediated inhibition of beta-catenin signaling, and the genetic interaction is conserved in zebrafish. This is a genuine regulatory role, but it is secondary to the transition-zone function. Supporting Evidence: PMID:22654112 The stabilization and nuclear translocation of Jade-1 by NPHP4 enhances the ability of Jade-1 to negatively regulate canonical Wnt signaling. PMID:22654112 Finally, NPHP4 and Jade-1 additively inhibit canonical Wnt signaling, and this genetic interaction is conserved in zebrafish. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IDA PMID:22654112 The ciliary protein nephrocystin-4 translocates the canonica... | KEEP AS NON CORE | Summary: NPHP4 inhibits canonical Wnt signaling by stabilizing JADE1 and translocating it to the nucleus. Reason: This is experimental evidence in human cells and zebrafish. It is kept as a non-core regulatory role. Supporting Evidence: PMID:22654112 NPHP4 stabilizes protein levels of Jade-1 and promotes the translocation of Jade-1 to the nucleus. PMID:22654112 The stabilization and nuclear translocation of Jade-1 by NPHP4 enhances the ability of Jade-1 to negatively regulate canonical Wnt signaling. PMID:22654112 Finally, NPHP4 and Jade-1 additively inhibit canonical Wnt signaling, and this genetic interaction is conserved in zebrafish. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based annotation of negative regulation of canonical Wnt signaling. Reason: This is consistent with the experimental data and is non-core. Supporting Evidence: PMID:22654112 The stabilization and nuclear translocation of Jade-1 by NPHP4 enhances the ability of Jade-1 to negatively regulate canonical Wnt signaling. |
| GO:0097470 ribbon synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-based annotation (from mouse) of NPHP4 at the photoreceptor ribbon synapse. Reason: The transfer presumably reflects an experimental localization of mouse Nphp4, which was not checked here. Mouse Nphp4 is needed for photoreceptor formation and maintenance. A synaptic pool would be a tissue-specific location separate from the ciliary role, so the annotation is kept as non-core and deferred to the mouse curators. Supporting Evidence: PMID:25150219 A study of Nphp4 -mutant mice has shown that Nphp4 is necessary for normal photoreceptor formation and maintenance as well as sperm development |
| GO:0097546 ciliary base | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference that NPHP4 acts at the ciliary base. Reason: This is correct. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies PMID:25150219 NPHP4 is stably incorporated into the distal part of the flagellar transition zone, close to the membrane and distal to CEP290, another transition zone protein. |
| GO:0097546 ciliary base | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based annotation of NPHP4 to the ciliary base. Reason: This is correct. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0097730 non-motile cilium | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference that NPHP4 localizes to non-motile (primary) cilia. Reason: NPHP4 sits at the transition zone of primary cilia. The term is acceptable but less precise than ciliary transition zone. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0097730 non-motile cilium | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation to the non-motile cilium. Reason: This is acceptable, as for the IBA. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:0098609 cell-cell adhesion | NAS PMID:12006559 Nephrocystin-conserved domains involved in targeting to epit... | MARK AS OVER ANNOTATED | Summary: A curator statement of a role in cell-cell adhesion, citing an NPHP1 paper. Reason: The cited abstract concerns NPHP1, not NPHP4. NPHP4 localizes to cell-cell contacts and supports timely tight-junction formation, but no direct role in adhesion between cells is shown. Junction assembly is captured more precisely elsewhere. Supporting Evidence: PMID:12006559 These findings support a functional role for nephrocystin as a docking protein involved in organizing a protein complex to regulate the actin cytoskeleton at sites of epithelial cell-cell adhesion PMID:19755384 these results indicate that nephrocystins-1 and -4 are required for the proper timing of tight junctional establishment necessary for the formation of a fully polarized epithelial monolayer |
| GO:0120206 photoreceptor distal connecting cilium | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based annotation of NPHP4 to the photoreceptor distal connecting cilium. Reason: This is acceptable and consistent with the connecting-cilium localization. Supporting Evidence: PMID:15661758 nephrocystin-4 also localizes to the primary cilia in polarized epithelial tubular cells, particularly at the basal bodies |
| GO:1903348 positive regulation of bicellular tight junction assembly | IMP PMID:19755384 Nephrocystin-1 and nephrocystin-4 are required for epithelia... | ACCEPT | Summary: NPHP4 knockdown in MDCK cells delays tight-junction formation. NPHP4 associates with PALS1/PATJ and PAR6. Reason: This is direct experimental evidence, corroborated by 3D spheroid assays in which loss of Nphp4 reduced ZO1-positive tight junctions. Supporting Evidence: PMID:19755384 these results indicate that nephrocystins-1 and -4 are required for the proper timing of tight junctional establishment necessary for the formation of a fully polarized epithelial monolayer PMID:21565611 cells depleted of Nphp1, Nphp4, Nphp8 and Nphp2 developed spheroids with irregular lumens, reduced sphericity, fewer ZO1 positive tight junctions |
| GO:1904491 protein localization to ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT inference that NPHP4 acts in protein localization to the ciliary transition zone. Reason: In Chlamydomonas, NPHP4 is required for the barrier that controls ciliary membrane and soluble protein composition. In C. elegans, NPHP-4 is required with the MKS module for transition-zone membrane attachment. This is core. Supporting Evidence: PMID:25150219 Therefore, NPHP4 functions at the transition zone as an essential part of a barrier that regulates both membrane and soluble protein composition of flagella. PMID:21422230 MKS-6 and NPHP-4 are collectively required for BB/TZ attachments to membrane. |
| GO:1904491 protein localization to ciliary transition zone | NAS PMID:28401750 The Ciliary Transition Zone: Finding the Pieces and Assembli... | ACCEPT | Summary: A transition-zone review places NPHP4 in transition-zone protein localization and assembly. Reason: This is correct and core. Supporting Evidence: PMID:28401750 However, combining the disruption of a MKS complex component with the disruption of NPHP1 or NPHP4 severely disrupted ciliogenesis, and ciliary functions PMID:28401750 suggesting that the known TZ modules are assembled, at least in part, prior to their incorporation into the TZ |
| GO:1990957 NPHP complex | NAS PMID:17558407 Mutations in the gene encoding the basal body protein RPGRIP... | ACCEPT | Summary: NPHP4 is part of the NPHP (NPHP1-4-8) complex. It bridges NPHP1 and RPGRIP1L. Reason: This is well supported by human proteomics and interaction mapping. Supporting Evidence: PMID:21565611 Our data show that NPHP-JBTS-MKS proteins form an interaction network that can be classified into three distinct modules PMID:17558407 We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. PMID:21565611 This NPHP1-4-8 compartment is reminiscent of the ciliary transition zone |
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Download this section (compressed HTML)Q: Does NPHP4 bind membrane lipids directly through its C2-like domains, which would explain how it holds the distal transition zone against the ciliary membrane?
Q: Are the Wnt (JADE1) and Hippo (LATS1) regulatory roles of NPHP4 carried out by the transition-zone pool or by separate cytoplasmic or nuclear pools?
Experiment: Use liposome flotation and lipid-strip assays with purified NPHP4 C2-like domains to test for direct phosphoinositide or membrane binding.
Experiment: Use human NPHP4-null RPE1 cells with combined MKS-module depletion and fluorescence recovery after photobleaching of ciliary membrane reporters to test whether the Chlamydomonas barrier function of NPHP4 is conserved in mammals.
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