ARMC9 is a Joubert syndrome-associated ciliary protein that coordinates a network of microtubule regulators, including TOGARAM1 and CSPP1. Distinct regions mediate partner interactions, and its central H region supports dimerization. Reconstitution shows partner-dependent recruitment and modulation of microtubule dynamics, without autonomous ARMC9 microtubule binding or polymerase activity. Endogenous human ARMC9 localizes near basal bodies and daughter centrioles; tagged ARMC9 also shows stimulus-dependent ciliary-tip enrichment in mouse cells. Disruption of ARMC9 impairs ciliary formation and stability, and biallelic variants cause Joubert syndrome. The location and composition of the active partner-coordinating network in cells remain incompletely resolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32453716 Dysfunction of the ciliary ARMC9/TOGARAM1 protein module cau... | KEEP AS NON CORE | Summary: CCDC66 association is supported by the original interaction assays. Reason: The 2020 study identifies CCDC66 by ARMC9 yeast two-hybrid screening and confirms association by tagged co-immunoprecipitation. These experiments support an interaction within the ciliary module; they do not establish a more specific ARMC9 activity for this pair. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32453716 Dysfunction of the ciliary ARMC9/TOGARAM1 protein module cau... | KEEP AS NON CORE | Summary: CEP104 coassociation is positive but condition dependent. Reason: Tagged co-immunoprecipitation in the 2020 study supports CEP104 association, although CEP104 was not an ARMC9 binary yeast two-hybrid positive. The 2025 study did not reproduce the weak co-immunoprecipitation. Retain the original positive association with this experimental discrepancy; a direct binary interface is unresolved. Supporting Evidence: PMID:39856351 no direct interaction has been described for ARMC9 and CEP104, even though they were previously shown to weakly coimmunoprecipitate with each other9, an observation we could not confirm |
| GO:0005515 protein binding | IPI PMID:32453716 Dysfunction of the ciliary ARMC9/TOGARAM1 protein module cau... | KEEP AS NON CORE | Summary: CSPP1 association is supported by the original interaction assays. Reason: CSPP1 is a binary Y2H interactor and a confirmed co-IP partner in the cited 2020 study. Its association with an ARMC9 coiled-coil/ARM-containing fragment helps define the module, but does not isolate a named CSPP1 target domain or justify assigning CSPP1 microtubule-binding chemistry to ARMC9. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32453716 Dysfunction of the ciliary ARMC9/TOGARAM1 protein module cau... | MODIFY | Summary: ARMC9 recognizes a TOG-domain-containing region of TOGARAM1. Reason: The original 2020 study maps ARMC9 binding to the TOGARAM1 N-terminal fragment containing TOG1 and TOG2. TOG2 substitutions R368W and L375P disrupt association, whereas the TOG3 substitution R1311C retains it in the reported interaction assays. Fragment mapping and these differential results support protein domain specific binding. They do not establish an isolated TOG2 interface or exclude an effect on folding; the later 2025 fine mapping is separate evidence. Proposed replacements: protein domain specific binding Supporting Evidence: file:human/ARMC9/ARMC9-notes.md The original 2020 Figures 1 and 3 map ARMC9 binding to the TOGARAM1 N-terminal TOG1/TOG2 fragment; R368W and L375P in TOG2 disrupt association, whereas R1311C in TOG3 retains it. These experiments support domain-specific recognition without proving an isolated TOG2 interface. |
| GO:0005515 protein binding | IPI PMID:38949024 Primary cilia formation requires the Leigh syndrome-associat... | KEEP AS NON CORE | Summary: NDUFAF2 associates with ARMC9 in human cell assays. Reason: The cited 2024 study demonstrates tagged human NDUFAF2–ARMC9 co-IP and maps association to the coiled-coil/ARM-containing ARMC9 region. PLA near basal bodies and mitochondria is proximity evidence. NDUFAF2 is a mitochondrial complex-I assembly factor, not evidence that ARMC9 performs respiratory chemistry or an intrinsic enzyme-binding mechanism. Supporting Evidence: PMID:38949024 identified NDUFAF2 as a binding partner for ARMC9. |
| GO:0005515 protein binding | IPI PMID:38949024 Primary cilia formation requires the Leigh syndrome-associat... | UNDECIDED | Summary: The TOGARAM1 pair is unresolved within this particular source. Reason: TOGARAM1 is an established ARMC9 partner in the 2020 and 2025 studies. In the cited 2024 paper, the inspected main text and figure legend establish NDUFAF2 association, and Methods list a human TOGARAM1 construct. The pair-labelled blot or supplementary TOGARAM1 experiment could not be inspected. The evidence for this particular IPI assertion therefore remains unresolved. |
| GO:0005814 centriole | IBA GO_REF:0000033 | ACCEPT | Summary: Centriole localization agrees with direct human evidence. Reason: Centriole localization is independently supported by endogenous human hTERT-RPE1 basal-body/daughter-centriole staining in PMID:28625504. This supports the biological placement of the IBA; the target as a descendant evidence source is expected, not circular. The precise PTN000382362 topology has not been reconstructed, so no additional node-level evolutionary claim is made. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0005814 centriole | IDA PMID:28625504 Mutations in ARMC9, which Encodes a Basal Body Protein, Caus... | ACCEPT | Summary: Endogenous human ARMC9 localizes to the daughter centriole. Reason: Original Figure 3 of PMID:28625504 explicitly localizes endogenous ARMC9 at the basal body and daughter centriole in serum-starved human hTERT-RPE1 cells, with centriole/cilium markers. This directly supports the existing human IDA location; the cache remains abstract-only despite the separate caption read. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0005814 centriole | IEA GO_REF:0000044 | ACCEPT | Summary: The mapped centriole location agrees with human staining. Reason: The UniProt subcellular-location mapping agrees with the directly observed endogenous human basal-body/daughter-centriole staining in PMID:28625504. It is appropriate for a ciliary structural protein and does not imply that ARMC9 is a centriole-building enzyme. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0005929 cilium | IEA GO_REF:0000044 | ACCEPT | Summary: ARMC9 has a dynamic ciliary pool. Reason: The broad cilium location is consistent with basal-body localization and the dynamic ciliary shaft/tip pool documented in mouse-cell studies. The UniProt mapping is retained without rewriting the original assertion into a human-specific tip experiment or assuming constitutive tip residence. Supporting Evidence: PMID:29459677 ARMC9-3xFLAG localized to the proximal region of cilia when stably expressed in IMCD3 or NIH-3T3 cells |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: Basal-body localization agrees with direct human evidence. Reason: The basal-body IBA agrees with endogenous human localization in PMID:28625504. Its human self-donor is legitimate evidence for ancestral placement, not circular support. No uninspected branch topology or taxon-loss conclusion is asserted. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0036064 ciliary basal body | IDA PMID:28625504 Mutations in ARMC9, which Encodes a Basal Body Protein, Caus... | ACCEPT | Summary: Endogenous human ARMC9 localizes to the ciliary basal body. Reason: The original human hTERT-RPE1 Figure 3 staining in PMID:28625504 identifies ARMC9 at the ciliary basal body, distinguished from the transition-zone marker and accompanied by daughter-centriole staining. This is a supported core ciliary location. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0036064 ciliary basal body | IEA GO_REF:0000002 | ACCEPT | Summary: The mapped basal-body location agrees with human staining. Reason: The InterPro-derived basal-body location agrees with the direct human observation and the conserved ciliary role of ARMC9. The mapping is accepted on the combined biological evidence; the InterPro entry has not been independently re-annotated or treated as a substitute for the human experiment. Supporting Evidence: PMID:28625504 We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. |
| GO:0042802 identical protein binding | IPI PMID:32453716 Dysfunction of the ciliary ARMC9/TOGARAM1 protein module cau... | ACCEPT | Summary: ARMC9 self-association supports its structural role. Reason: The 2020 interaction assays support ARMC9 self-association and map it to the N-terminal 350-residue region. Independent 2025 single-molecule experiments identify dimerization dependent on the central H region. TOGARAM1 recognition maps independently of H, so dimerization is not assumed to be required for every partner interaction. Supporting Evidence: PMID:39856351 single-molecule counting experiments showed that ARMC9 forms dimers dependent on its central H region |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Hedgehog signaling is a downstream context of the ciliary module. Reason: The existing ortholog transfer is consistent with the 2018 mouse-cell Armc9 loss-of-function effects on Hedgehog output and GLI2/GLI3 ciliary-tip accumulation. Retain the pathway consequence as a signaling context of ciliary structure, with mouse endogenous experiments and unresolved tagged-reagent species explicit. Do not infer direct SMO binding, GLI motor activity or a signaling enzyme. Supporting Evidence: PMID:29459677 Armc9 mutant NIH-3T3 cells exhibited reduced ciliary accumulation of GLI2 and GLI3 (but not SMO) upon pathway activation |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: ARMC9 contributes to cilium formation and stability. Reason: The cilium-assembly IBA agrees with zebrafish perturbation, abnormal cilia in human patient cells and ARMC9-mediated coordination of ciliary microtubule regulators. Together these support participation in building and maintaining ciliary structure. The exact ancestral placement has not been independently reconstructed. Supporting Evidence: PMID:32453716 Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability. |
| GO:0060271 cilium assembly | IEA GO_REF:0000002 | ACCEPT | Summary: The mapped cilium-assembly role agrees with the structural evidence. Reason: The InterPro-derived cilium-assembly assertion agrees with the conserved structural role and human/fish phenotypes. It is retained without assigning intrinsic tubulin polymerase, acetyltransferase or glutamylase activity to ARMC9. Supporting Evidence: PMID:32453716 Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: The curated cilium-assembly transfer agrees with the conserved role. Reason: The curated ortholog transfer agrees with ciliary abnormalities in human patient cells and the conserved ARMC9 protein network. The precise assay underlying the E7F187 donor has not been independently inspected. Supporting Evidence: PMID:32453716 Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: The curated cilium-assembly transfer agrees with the conserved role. Reason: The curated ortholog transfer agrees with the human and zebrafish ciliary evidence and biochemical coordination of ciliary proteins. The precise Q6P6J9 donor experiment has not been independently inspected. Supporting Evidence: PMID:32453716 Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytoplasmic ciliary basal-body protein. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.) |
| GO:0097542 ciliary tip | IBA GO_REF:0000033 | ACCEPT | Summary: Tip localization is supported with conditional mammalian scope. Reason: The ciliary-tip IBA is consistent with the 2018 mouse-cell time course showing conditional ARMC9 tip enrichment after Hedgehog stimulation and its conserved module role. The precise PAINT node topology has not been reconstructed. This does not establish constitutive human tip residence or assign tagged reagent species from its host. Supporting Evidence: PMID:29459677 stimulation of Hh signaling in IMCD3 cells led to redistribution of ARMC9 towards the ciliary tip within 6 hr before a gradual return to its original proximal location |
| GO:0097542 ciliary tip | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse-ortholog tip-localization transfer is supported. Reason: The mouse-ortholog transfer is supported by the 2018 mouse-cell study: tagged ARMC9 redistributes from the proximal cilium to the tip after Hedgehog stimulation, then returns toward its original distribution. This supports conditional tip localization, without establishing constitutive human tip residence. Supporting Evidence: PMID:29459677 stimulation of Hh signaling in IMCD3 cells led to redistribution of ARMC9 towards the ciliary tip within 6 hr before a gradual return to its original proximal location |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:39856351 A network of interacting ciliary tip proteins with opposing ... | NEW | Summary: ARMC9 coordinates TOGARAM1 and CSPP1 through distinct binding regions. Reason: Reconstituted human ARMC9 binds TOGARAM1 and CSPP1 through distinct regions, is recruited by these partners and modifies their effects on microtubule dynamics. This supports bringing macromolecules together for coordinated function. The assays combine human ARMC9, mouse TOGARAM1 and porcine tubulin. An integral ARMC9 structural position in the assembled complex has not been resolved, so adaptor activity is the more conservative description of this author-added assertion. Scaffold activity remains plausible; flexible stoichiometry and mild effects of individual depletion do not refute it. No autonomous microtubule-binding or polymerase activity is assigned to ARMC9. Supporting Evidence: PMID:39856351 ARMC9 can bind to both proteins through two distinct domains and mildly enhance their effects on MT dynamics PMID:39856351 For all module members except TOGARAM1, the human sequence was used; because of technical difficulties, the mouse sequence of TOGARAM1 was used, which is 84% identical to human TOGARAM1. |
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Download this section (compressed HTML)Q: At which cellular sites does ARMC9 coordinate TOGARAM1 and CSPP1, and what experiments distinguish the adaptor activity from the protein distributions at basal bodies, daughter centrioles and ciliary tips?
Q: Which experimental conditions explain the differing CEP104–ARMC9 co-IP observations in the 2020 and 2025 studies?
Q: How does NDUFAF2 association connect mitochondrial state to ciliary stability without assigning respiratory enzyme activity to ARMC9?
Q: Do the original 2024 TOGARAM1 experiment and urinary-exosome peptide record verify their precise source-local ARMC9 assertions?
Experiment: Compare accession-defined human ARMC9 isoforms in endogenous localization and purified partner-recruitment assays, varying TOGARAM1/CSPP1/CCDC66 ratios and separating dimerization from each binding interface.
Experiment: Test ARMC9 complex composition at basal bodies and at stimulated ciliary tips, alongside cilium growth and resorption measurements, to distinguish structural organization from downstream signaling effects.
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