RPGRIP1L (also called NPHP8, MKS5 or FTM) is a large coiled-coil and C2-domain protein of the ciliary transition zone, related to the photoreceptor protein RPGRIP1. It sits at the basal body and transition zone, distal to CEP290, and binds NPHP4 directly as part of the NPHP1-NPHP4-NPHP8 module. RPGRIP1L acts as the upstream scaffold for assembling the transition zone: MKS- and NPHP-module proteins depend on it to reach the transition zone and form the ciliary diffusion barrier. In photoreceptors it binds RPGR at the connecting cilium, and the common A229T variant, which weakens RPGR binding, modifies retinal degeneration. Loss of RPGRIP1L causes Joubert syndrome, Meckel syndrome and nephronophthisis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:19430481 A common allele in RPGRIP1L is a modifier of retinal degener... | REMOVE | Summary: RPGRIP1L interaction with human RPGR. Y2H and co-IP identify the RPGRIP1L C-terminal RPGR-interacting domain; the A229T variant weakens binding. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. Supporting Evidence: PMID:19430481 Co-transfection of COS-1 cells followed by co-IP demonstrated that Xpress-tagged RPGR and GFP-RPGRIP1L proteins are part of the same complex PMID:19430481 Triplicate experiments showed that the GFP-tagged A229T mutant protein showed considerably lower (∼80%) ability to immunoprecipitate RPGR |
| GO:0005515 protein binding | IPI PMID:19430481 A common allele in RPGRIP1L is a modifier of retinal degener... | REMOVE | Summary: RPGRIP1L interaction with mouse Rpgr. Reciprocal co-immunoprecipitation from retina in the same study. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. Supporting Evidence: PMID:19430481 Co-transfection of COS-1 cells followed by co-IP demonstrated that Xpress-tagged RPGR and GFP-RPGRIP1L proteins are part of the same complex |
| GO:0005515 protein binding | IPI PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | REMOVE | Summary: RPGRIP1L interaction with NPHP4. LAP-tag purification and in vitro binding show NPHP4 binds RPGRIP1L (NPHP8) directly within the NPHP1-4-8 module. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. Supporting Evidence: PMID:21565611 We find that NPHP4 directly binds both NPHP1 and NPHP8 in vitro PMID:21565611 LAP-NPHP8 showed high efficiency interactions with NPHP1 and NPHP4 (Figure 2A). |
| GO:0005515 protein binding | IPI PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | REMOVE | Summary: RPGRIP1L interaction with IQCB1 (NPHP5). Detected by co-IP in HEK293T cells; the authors note the interaction likely requires bridging proteins. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: RPGRIP1L interaction with NPHP4. BioID proximity hit in the centrosome-cilium interface map. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. |
| GO:0005515 protein binding | IPI PMID:30471718 Recessive DNAH9 Loss-of-Function Mutations Cause Laterality ... | REMOVE | Summary: RPGRIP1L interaction with NPHP4. RPGRIP1L C-terminal fragment used as the positive-control NPHP4 binder in this study. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. Supporting Evidence: PMID:30471718 NPHP4-3xHA and RPGRIP1L-C-term-3xFLAG were used as positive control |
| GO:0005515 protein binding | IPI PMID:40739040 Multi-proteomic profiling of the varicella-zoster virus-host... | REMOVE | Summary: RPGRIP1L interaction with NPHP4. Detected in a large virus-host proteomic interaction screen. Reason: GO:0005515 protein binding records that an interaction was detected but not what RPGRIP1L does. The interactions are credible and are better represented by NPHP complex membership and transition-zone localization. Removing the generic binding term does not mean the interaction is false; the assays do not support a more informative molecular-function term. |
| GO:0005737 cytoplasm | IDA PMID:17558409 The ciliary gene RPGRIP1L is mutated in cerebello-oculo-rena... | KEEP AS NON CORE | Summary: Cytoplasmic signal for RPGRIP1L. Reason: A cytoplasmic pool is plausible for this soluble protein, but the functionally relevant location is the ciliary transition zone/basal body. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined electronic annotation of cytoplasm. Reason: Broad compartment, retained as non-core. |
| GO:0005813 centrosome | IDA PMID:17558409 The ciliary gene RPGRIP1L is mutated in cerebello-oculo-rena... | ACCEPT | Summary: RPGRIP1L colocalizes with NPHP6 and NPHP4 at basal bodies and centrosomes. Reason: Direct localization evidence; centrosome/basal body is the anchor of the transition zone. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0005813 centrosome | IDA PMID:21399614 Novel asymmetrically localizing components of human centroso... | ACCEPT | Summary: Centrosome proteomic/localization screen identifies RPGRIP1L at centrosomes. Reason: Consistent with other localization studies. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to centrosome. Reason: Consistent with experimental data. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence (HPA) cytosol signal. Reason: Broad cytosolic staining is compatible with a soluble pool but not the functional location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | KEEP AS NON CORE | Summary: Reactome cytosol location in the RAB8A nucleotide exchange event. Reason: Broad compartment; GEF activity belongs to RAB3IP. Supporting Evidence: Reactome:R-HSA-5617816 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | KEEP AS NON CORE | Summary: Reactome cytosol location in recruitment of transition zone proteins. Reason: Event is apt for RPGRIP1L, but cytosol is a broad compartment; TZ is the informative location. Supporting Evidence: Reactome:R-HSA-5626681 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | KEEP AS NON CORE | Summary: Reactome cytosol location in CEP164-mediated vesicle recruitment. Reason: Broad compartment from an event whose activities belong to other participants. Supporting Evidence: Reactome:R-HSA-5638009 |
| GO:0005911 cell-cell junction | IDA PMID:21565611 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy... | KEEP AS NON CORE | Summary: NPHP1-4-8 module proteins localize to cell-cell contacts in addition to the TZ. Reason: Experimentally observed second location of the NPHP module in epithelial cells, peripheral to the ciliary function. Supporting Evidence: PMID:21565611 The first module consists of NPHP1, NPHP4 and NPHP8, localized to cell-cell contacts and to the ciliary transition zone. |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt mapping to bicellular tight junction. Reason: Derived from the cell-contact localization of the NPHP1-4-8 module; the tight-junction assignment is more specific than the cited cell-contact data show, but it is retained as a non-core location. Supporting Evidence: PMID:21565611 The first module consists of NPHP1, NPHP4 and NPHP8, localized to cell-cell contacts and to the ciliary transition zone. |
| GO:0005929 cilium | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence curation of cilium localization. Reason: TZ is part of the cilium. |
| GO:0005929 cilium | IDA PMID:17558409 The ciliary gene RPGRIP1L is mutated in cerebello-oculo-rena... | ACCEPT | Summary: RPGRIP1L localizes to the cilium base. Reason: Consistent with TZ localization. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0005930 axoneme | IDA PMID:17558409 The ciliary gene RPGRIP1L is mutated in cerebello-oculo-rena... | KEEP AS NON CORE | Summary: RPGRIP1L reported along the axoneme. Reason: RPGRIP1L is concentrated in the transition zone at the proximal axoneme. Axonemal signal beyond the TZ is not its principal location, but the curated observation is retained as non-core. Supporting Evidence: PMID:28401750 RPGRIP1L was distal to CEP290 and presented a similar width. |
| GO:0005930 axoneme | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt mapping to axoneme. Reason: As above; TZ is the principal location. Supporting Evidence: PMID:28401750 RPGRIP1L was distal to CEP290 and presented a similar width. |
| GO:0009966 regulation of signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of regulation of signal transduction. Reason: Very broad. RPGRIP1L affects cilium-dependent signalling (and TP receptor signalling in one overexpression study), but these effects follow from its TZ structural role rather than signal-transduction activity. Supporting Evidence: PMID:19464661 TP-mediated phosphoinositide hydrolysis, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and interleukin-6 production were reduced by the expression of KIAA1005/TPIP |
| GO:0031870 thromboxane A2 receptor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference of thromboxane A2 receptor binding, seeded by the human RPGRIP1L experiment. Reason: The IBA rests on the human Y2H/co-IP data (the target appears in its own WITH/FROM, which is expected). The interaction is real in that assay but has not been placed in the ciliary context, and it is not the conserved core role. Supporting Evidence: PMID:19464661 We found KIAA1005 as a novel interacting protein of the TP alpha and TP beta C-terminal region |
| GO:0031870 thromboxane A2 receptor binding | IPI PMID:19464661 Thromboxane A2-induced signal transduction is negatively reg... | KEEP AS NON CORE | Summary: RPGRIP1L (KIAA1005/TPIP) binds the C-terminal tail of TP alpha and TP beta. Reason: Y2H plus co-IP in HEK293 cells support a specific receptor-binding activity, but it is a single overexpression study and peripheral to the transition-zone function. Supporting Evidence: PMID:19464661 We found KIAA1005 as a novel interacting protein of the TP alpha and TP beta C-terminal region |
| GO:0032391 photoreceptor connecting cilium | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of photoreceptor connecting cilium localization. Reason: The connecting cilium is the photoreceptor transition zone; RPGRIP1L variants modify retinal degeneration through RPGR interaction there. Supporting Evidence: PMID:19430481 Triplicate experiments showed that the GFP-tagged A229T mutant protein showed considerably lower (∼80%) ability to immunoprecipitate RPGR |
| GO:0035869 ciliary transition zone | IDA PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | ACCEPT | Summary: RPGRIP1L localizes to the ciliary transition zone. Reason: Core location. Supporting Evidence: PMID:28401750 RPGRIP1L was distal to CEP290 and presented a similar width. |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic transfer of TZ location from mouse. Reason: Core location. Supporting Evidence: PMID:28401750 RPGRIP1L was distal to CEP290 and presented a similar width. |
| GO:0035869 ciliary transition zone | NAS PMID:28401750 The Ciliary Transition Zone: Finding the Pieces and Assembli... | ACCEPT | Summary: Review places RPGRIP1L in the TZ distal to CEP290. Reason: Core location. Supporting Evidence: PMID:28401750 RPGRIP1L was distal to CEP290 and presented a similar width. |
| GO:0036064 ciliary basal body | IDA PMID:17558409 The ciliary gene RPGRIP1L is mutated in cerebello-oculo-rena... | ACCEPT | Summary: RPGRIP1L localizes to basal bodies. Reason: Direct localization evidence. Supporting Evidence: PMID:17558409 RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4 |
| GO:0036064 ciliary basal body | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic transfer of basal body location. Reason: Consistent with experimental data. Supporting Evidence: PMID:17558407 its protein product localizes to basal bodies |
| GO:0045744 negative regulation of G protein-coupled receptor signaling pathway | IDA PMID:19464661 Thromboxane A2-induced signal transduction is negatively reg... | KEEP AS NON CORE | Summary: RPGRIP1L overexpression reduces TP receptor surface levels and TP-mediated signalling. Reason: Experimental but single-study overexpression evidence. It is retained as a peripheral role and is not representative of RPGRIP1L's conserved transition-zone function. Supporting Evidence: PMID:19464661 TP-mediated phosphoinositide hydrolysis, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and interleukin-6 production were reduced by the expression of KIAA1005/TPIP |
| GO:1904491 protein localization to ciliary transition zone | NAS PMID:28401750 The Ciliary Transition Zone: Finding the Pieces and Assembli... | ACCEPT | Summary: RPGRIP1L is required for recruitment of MKS and NPHP module proteins to the TZ. Reason: Core process: MKS-5/RPGRIP1L is the upstream assembly hub on which TZ module recruitment depends, a role described in worm and mouse. Supporting Evidence: PMID:28401750 A strong genetic interaction was also observed between MKS5/RPGRIP1L and components of both the MKS and NPHP modules which rely on it for their recruitment to the TZ PMID:26982032 MKS-5 (mammalian Rprgrip1L/Rpgrip1 orthologue) is essential for the assembly of all known TZ proteins (including CEP-290) |
| GO:1905515 non-motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of non-motile cilium assembly. Reason: Rpgrip1l loss in mouse recapitulates ciliopathy phenotypes, and the worm ortholog is needed to build the TZ of non-motile sensory cilia. Supporting Evidence: PMID:17558409 inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS PMID:26982032 MKS-5 (mammalian Rprgrip1L/Rpgrip1 orthologue) is essential for the assembly of all known TZ proteins (including CEP-290) |
| GO:1990957 NPHP complex | NAS PMID:17558407 Mutations in the gene encoding the basal body protein RPGRIP... | ACCEPT | Summary: RPGRIP1L (NPHP8) is part of the NPHP1-NPHP4-NPHP8 module. Reason: Biochemical purification shows NPHP1, NPHP4 and NPHP8 form a module, with NPHP4 binding RPGRIP1L directly. Supporting Evidence: PMID:21565611 The first module consists of NPHP1, NPHP4 and NPHP8, localized to cell-cell contacts and to the ciliary transition zone. PMID:21565611 We find that NPHP4 directly binds both NPHP1 and NPHP8 in vitro |
| GO:1905349 ciliary transition zone assembly | ISS PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr... | NEW | Summary: RPGRIP1L/MKS-5 is the upstream scaffold required to assemble the transition zone. Reason: Participation test: MKS-5/RPGRIP1L does part of the work of TZ assembly as a structural scaffold. The other TZ proteins, CEP-290 included, depend on it for localization, so RPGRIP1L is more than a component the process uses. Comparator: CEP290 already carries GO:1905349 by IBA, and RPGRIP1L acts upstream of CEP290 in the same hierarchy. The direct evidence is from the C. elegans ortholog with mammalian genetic support. The assertion is made at the assembly-process level; the TZ-localization process term is already annotated. Supporting Evidence: PMID:26982032 MKS-5 (mammalian Rprgrip1L/Rpgrip1 orthologue) is essential for the assembly of all known TZ proteins (including CEP-290) PMID:26982032 Another established TZ protein, MKS-5 (RPGRIP1L/MKS5), is thought to act as a “scaffold” or “assembly factor” for most, if not all, MKS and NPHP module proteins PMID:28401750 A strong genetic interaction was also observed between MKS5/RPGRIP1L and components of both the MKS and NPHP modules which rely on it for their recruitment to the TZ |
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Download this section (compressed HTML)Q: Is human RPGRIP1L, like worm MKS-5, required for TZ localization of CEP290, or is the CEP290-RPGRIP1L hierarchy different in mammals?
Q: Does the RPGRIP1L-TBXA2R interaction occur at endogenous levels in ciliated cells, and is it relevant to ciliary GPCR handling?
Experiment: In RPGRIP1L-knockout human RPE1 cells, quantify TZ recruitment of CEP290, NPHP1/4 and MKS-module proteins by STED/expansion microscopy, and rescue with coiled-coil and C2-domain deletion constructs.
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