TMEM216 is a small tetraspan transmembrane protein of the MKS (tectonic) module of the ciliary transition zone. It localizes to the ciliary base/transition zone between the axonemal microtubules and the ciliary membrane, and also marks post-Golgi vesicles that move toward the ciliary base together with TMEM138-positive vesicles. It associates with TCTN1, meckelin (TMEM67), TMEM107 and other MKS-module proteins, and is required for primary ciliogenesis, for apical docking of the centrosome/basal body in polarized epithelial cells, and for cilium-dependent signalling including Hedgehog signalling. Loss-of-function variants cause Joubert syndrome 2, Meckel syndrome 2 and related disorders (including oral-facial-digital type VI), and retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | REMOVE | Summary: High-confidence interaction of TMEM216 with TMEM107 reported in a study defining TMEM107 as an MKS-module transition zone protein. Reason: Generic protein binding is uninformative; the TMEM107 association reflects co-membership of the MKS transition-zone module, which is already captured by the MKS complex (GO:0036038) and ciliary transition zone annotations. Removal does not dispute the interaction. No specific molecular activity can be inferred from it. Supporting Evidence: PMID:26595381 Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | REMOVE | Summary: Reactome cilium-assembly reactions place TMEM216 in the cytosol. Reason: TMEM216 is a small tetraspan (multi-pass) membrane protein. Experimentally it is found at the ciliary base/transition zone and on post-Golgi vesicles and Golgi membranes, never as a soluble cytosolic protein. The cytosol assignment is an artefact of how the Reactome reaction compartments are represented. Supporting Evidence: PMID:22282472 It is noteworthy that TMEM216 localized to post-Golgi vesicles along microtubules, as well as the Golgi apparatus surrounding the base of cilium PMID:22282472 Immunostaining of endogenous TMEM138 with a marker (Arl13b) of the ciliary axoneme and transition zone demonstrated closely adjacent localization with TMEM216 at the base of cilia |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | REMOVE | Summary: Reactome cilium-assembly reactions place TMEM216 in the cytosol. Reason: TMEM216 is a small tetraspan (multi-pass) membrane protein. Experimentally it is found at the ciliary base/transition zone and on post-Golgi vesicles and Golgi membranes, never as a soluble cytosolic protein. The cytosol assignment is an artefact of how the Reactome reaction compartments are represented. Supporting Evidence: PMID:22282472 It is noteworthy that TMEM216 localized to post-Golgi vesicles along microtubules, as well as the Golgi apparatus surrounding the base of cilium PMID:22282472 Immunostaining of endogenous TMEM138 with a marker (Arl13b) of the ciliary axoneme and transition zone demonstrated closely adjacent localization with TMEM216 at the base of cilia |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | REMOVE | Summary: Reactome cilium-assembly reactions place TMEM216 in the cytosol. Reason: TMEM216 is a small tetraspan (multi-pass) membrane protein. Experimentally it is found at the ciliary base/transition zone and on post-Golgi vesicles and Golgi membranes, never as a soluble cytosolic protein. The cytosol assignment is an artefact of how the Reactome reaction compartments are represented. Supporting Evidence: PMID:22282472 It is noteworthy that TMEM216 localized to post-Golgi vesicles along microtubules, as well as the Golgi apparatus surrounding the base of cilium PMID:22282472 Immunostaining of endogenous TMEM138 with a marker (Arl13b) of the ciliary axoneme and transition zone demonstrated closely adjacent localization with TMEM216 at the base of cilia |
| GO:0005929 cilium | IDA PMID:22282472 Evolutionarily assembled cis-regulatory module at a human ci... | ACCEPT | Summary: Endogenous TMEM216 localizes to the base of primary cilia, adjacent to TMEM138, in ciliated cells. Reason: IDA from Lee et al. 2012, corroborated by Valente et al. 2010 antibody staining at the ciliary base in kidney. Ciliary transition zone is the more precise location, but cilium is correct. Supporting Evidence: PMID:22282472 Immunostaining of endogenous TMEM138 with a marker (Arl13b) of the ciliary axoneme and transition zone demonstrated closely adjacent localization with TMEM216 at the base of cilia PMID:20512146 TMEM216 antibody also reacted strongly to the base of cilia in organs like kidney containing ciliated cells |
| GO:0008594 photoreceptor cell morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from zebrafish tmem216, whose loss causes photoreceptor outer-segment morphogenesis defects. Reason: Photoreceptor outer segments are modified primary cilia that depend on the connecting-cilium transition zone, so outer-segment defects follow from TZ dysfunction. Plausible, and consistent with retinal involvement in TMEM216 ciliopathy (Joubert syndrome 2, retinitis pigmentosa 98), but it is a tissue-specific consequence of the core TZ role, not a separate function. Supporting Evidence: PMID:20512146 We observed identical ciliary phenotypes in tmem216 morphants, which were largely rescued by RNA encoding human TMEM216 |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: TMEM216 is a predicted multi-pass (tetraspan) membrane protein. Reason: Correct general location; transition-zone membrane is the informative location. Supporting Evidence: PMID:26595381 Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. |
| GO:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: TMEM216 localizes to the ciliary base and the transition zone as an MKS-module membrane protein. Reason: Core location. Mouse Tmem216 is found at the TZ/basal body (Garcia-Gonzalo 2011), human TMEM216 at the ciliary base (Lee 2012; Valente 2010), and MKS-complex components including TMEM216 sit between the axonemal microtubules and the ciliary membrane (TZ review). The worm ortholog MKS-2 is a 'core' TZ protein whose localization depends on the other MKS proteins. Supporting Evidence: PMID:28401750 CBY partially overlapped with CEP290 whereas MKS complex components (Tectonic, MKS1, TMEM216, B9D1 and B9D2) localized between the axonemal MTs and the ciliary membrane PMID:21725307 Tmem216 occasionally localized to the transition zone, but more typically localized to the basal body or axoneme. PMID:26982032 Since MKS-1/MKSR-1/MKSR-2/MKS-2/TMEM-231 all depend on each other for their TZ localisation file:human/TMEM216/TMEM216-deep-research-falcon.md It is **not established as an enzyme, an ion transporter, or a transporter with a defined substrate**; the domain annotation predicts membrane topology, not catalytic or substrate specificity. |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM216 localizes to the ciliary base and the transition zone as an MKS-module membrane protein. Reason: Core location. Mouse Tmem216 is found at the TZ/basal body (Garcia-Gonzalo 2011), human TMEM216 at the ciliary base (Lee 2012; Valente 2010), and MKS-complex components including TMEM216 sit between the axonemal microtubules and the ciliary membrane (TZ review). The worm ortholog MKS-2 is a 'core' TZ protein whose localization depends on the other MKS proteins. Supporting Evidence: PMID:28401750 CBY partially overlapped with CEP290 whereas MKS complex components (Tectonic, MKS1, TMEM216, B9D1 and B9D2) localized between the axonemal MTs and the ciliary membrane PMID:21725307 Tmem216 occasionally localized to the transition zone, but more typically localized to the basal body or axoneme. PMID:26982032 Since MKS-1/MKSR-1/MKSR-2/MKS-2/TMEM-231 all depend on each other for their TZ localisation file:human/TMEM216/TMEM216-deep-research-falcon.md It is **not established as an enzyme, an ion transporter, or a transporter with a defined substrate**; the domain annotation predicts membrane topology, not catalytic or substrate specificity. |
| GO:0035869 ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: TMEM216 localizes to the ciliary base and the transition zone as an MKS-module membrane protein. Reason: Core location. Mouse Tmem216 is found at the TZ/basal body (Garcia-Gonzalo 2011), human TMEM216 at the ciliary base (Lee 2012; Valente 2010), and MKS-complex components including TMEM216 sit between the axonemal microtubules and the ciliary membrane (TZ review). The worm ortholog MKS-2 is a 'core' TZ protein whose localization depends on the other MKS proteins. Supporting Evidence: PMID:28401750 CBY partially overlapped with CEP290 whereas MKS complex components (Tectonic, MKS1, TMEM216, B9D1 and B9D2) localized between the axonemal MTs and the ciliary membrane PMID:21725307 Tmem216 occasionally localized to the transition zone, but more typically localized to the basal body or axoneme. PMID:26982032 Since MKS-1/MKSR-1/MKSR-2/MKS-2/TMEM-231 all depend on each other for their TZ localisation file:human/TMEM216/TMEM216-deep-research-falcon.md It is **not established as an enzyme, an ion transporter, or a transporter with a defined substrate**; the domain annotation predicts membrane topology, not catalytic or substrate specificity. |
| GO:0036038 MKS complex | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM216 is a component of the MKS (tectonic) complex at the transition zone. Reason: TMEM216 co-immunoprecipitates with Tctn1 and is part of the Tctn1/MKS complex, though probably as a substoichiometric or peripheral member. It also forms a complex with meckelin (TMEM67). Supporting Evidence: PMID:21725307 By combining developmental, genetic, and biochemical analyses, we have identified a complex containing Tctn1, Tctn3 and seven MKS proteins (Mks1, Tmem216, Tmem67, Cep290, Cc2d2a, B9d1 and Tctn2). PMID:21725307 Thus, Cep290, Tmem67 and Tmem216 may be substoichiometric or peripheral components of the Tectonic complex. PMID:20512146 Both assays detected a complex between TMEM216 and Meckelin. |
| GO:0036038 MKS complex | ISS GO_REF:0000024 | ACCEPT | Summary: TMEM216 is a component of the MKS (tectonic) complex at the transition zone. Reason: TMEM216 co-immunoprecipitates with Tctn1 and is part of the Tctn1/MKS complex, though probably as a substoichiometric or peripheral member. It also forms a complex with meckelin (TMEM67). Supporting Evidence: PMID:21725307 By combining developmental, genetic, and biochemical analyses, we have identified a complex containing Tctn1, Tctn3 and seven MKS proteins (Mks1, Tmem216, Tmem67, Cep290, Cc2d2a, B9d1 and Tctn2). PMID:21725307 Thus, Cep290, Tmem67 and Tmem216 may be substoichiometric or peripheral components of the Tectonic complex. PMID:20512146 Both assays detected a complex between TMEM216 and Meckelin. |
| GO:0036038 MKS complex | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: TMEM216 is a component of the MKS (tectonic) complex at the transition zone. Reason: TMEM216 co-immunoprecipitates with Tctn1 and is part of the Tctn1/MKS complex, though probably as a substoichiometric or peripheral member. It also forms a complex with meckelin (TMEM67). Supporting Evidence: PMID:21725307 By combining developmental, genetic, and biochemical analyses, we have identified a complex containing Tctn1, Tctn3 and seven MKS proteins (Mks1, Tmem216, Tmem67, Cep290, Cc2d2a, B9d1 and Tctn2). PMID:21725307 Thus, Cep290, Tmem67 and Tmem216 may be substoichiometric or peripheral components of the Tectonic complex. PMID:20512146 Both assays detected a complex between TMEM216 and Meckelin. |
| GO:0045494 photoreceptor cell maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from zebrafish tmem216; loss impairs photoreceptor survival. Reason: As for photoreceptor morphogenesis, this is a tissue-level consequence of TZ/connecting-cilium dysfunction. It is consistent with retinal degeneration in TMEM216-related disease. Supporting Evidence: PMID:20512146 We observed identical ciliary phenotypes in tmem216 morphants, which were largely rescued by RNA encoding human TMEM216 |
| GO:0045724 positive regulation of cilium assembly | IEA GO_REF:0000107 | MODIFY | Summary: Transferred from mouse Tmem216; loss reduces ciliogenesis. Reason: The evidence (knockdown abolishes ciliogenesis) shows that TMEM216 is a required participant in cilium assembly, as a structural transition-zone component. Nothing shows that it modulates the rate or extent of assembly as a regulator. Cilium assembly (GO:0060271) is the appropriate term and is already annotated by IMP. Proposed replacements: cilium assembly Supporting Evidence: PMID:20512146 Tmem216 knockdown prevented ciliogenesis in polarized cells, and blocked correct docking of centrosomes at the apical cell surface PMID:22282472 suggesting that both TMEM138 and TMEM216 are required for ciliogenesis |
| GO:0045724 positive regulation of cilium assembly | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from mouse Tmem216; loss reduces ciliogenesis. Reason: The evidence (knockdown abolishes ciliogenesis) shows that TMEM216 is a required participant in cilium assembly, as a structural transition-zone component. Nothing shows that it modulates the rate or extent of assembly as a regulator. Cilium assembly (GO:0060271) is the appropriate term and is already annotated by IMP. Proposed replacements: cilium assembly Supporting Evidence: PMID:20512146 Tmem216 knockdown prevented ciliogenesis in polarized cells, and blocked correct docking of centrosomes at the apical cell surface PMID:22282472 suggesting that both TMEM138 and TMEM216 are required for ciliogenesis |
| GO:0045880 positive regulation of smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from mouse Tmem216, reported to promote Hedgehog signalling (including effects on SUFU-GLI interactions). Reason: Requirement of TMEM216 for Hedgehog signalling is consistent with its role in ciliogenesis and the ciliary gate. The proposed direct effect on SUFU-GLI complexes comes from by-similarity transfer and is not yet corroborated in human cells, so keep as non-core. Supporting Evidence: PMID:22179047 The complex that we have described is essential for normal cilia function and acts as a diffusion barrier to maintain the cilia membrane as a compartmentalized signalling organelle. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Tmem216, reported to promote Hedgehog signalling (including effects on SUFU-GLI interactions). Reason: Requirement of TMEM216 for Hedgehog signalling is consistent with its role in ciliogenesis and the ciliary gate. The proposed direct effect on SUFU-GLI complexes comes from by-similarity transfer and is not yet corroborated in human cells, so keep as non-core. Supporting Evidence: PMID:22179047 The complex that we have described is essential for normal cilia function and acts as a diffusion barrier to maintain the cilia membrane as a compartmentalized signalling organelle. |
| GO:0060271 cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM216 is required for primary ciliogenesis: knockdown in IMCD3 cells and patient (R85X) fibroblasts abolishes cilia formation, and zebrafish morphants show ciliary phenotypes rescued by human TMEM216. Reason: Strong functional evidence from human, mouse cell and zebrafish experiments (Valente 2010; Lee 2012). Supporting Evidence: PMID:20512146 Tmem216 knockdown prevented ciliogenesis in polarized cells, and blocked correct docking of centrosomes at the apical cell surface PMID:22282472 suggesting that both TMEM138 and TMEM216 are required for ciliogenesis PMID:20512146 We observed identical ciliary phenotypes in tmem216 morphants, which were largely rescued by RNA encoding human TMEM216 |
| GO:0060271 cilium assembly | IMP PMID:22282472 Evolutionarily assembled cis-regulatory module at a human ci... | ACCEPT | Summary: TMEM216 is required for primary ciliogenesis: knockdown in IMCD3 cells and patient (R85X) fibroblasts abolishes cilia formation, and zebrafish morphants show ciliary phenotypes rescued by human TMEM216. Reason: Strong functional evidence from human, mouse cell and zebrafish experiments (Valente 2010; Lee 2012). Supporting Evidence: PMID:20512146 Tmem216 knockdown prevented ciliogenesis in polarized cells, and blocked correct docking of centrosomes at the apical cell surface PMID:22282472 suggesting that both TMEM138 and TMEM216 are required for ciliogenesis PMID:20512146 We observed identical ciliary phenotypes in tmem216 morphants, which were largely rescued by RNA encoding human TMEM216 |
| GO:1904491 protein localization to ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: NAS based on Chih et al. (2011), which describes interdependent TZ localization of MKS-complex proteins. Reason: Within the MKS module, core membrane components depend on each other for TZ localization; the worm ortholog MKS-2 is one of the mutually dependent 'core' proteins. TMEM216 therefore participates in localizing MKS-module proteins to the TZ. Supporting Evidence: PMID:26982032 Since MKS-1/MKSR-1/MKSR-2/MKS-2/TMEM-231 all depend on each other for their TZ localisation |
| GO:1905515 non-motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: non-motile (primary) cilium assembly, inherited from the TMEM216/MKS-2 family node. Reason: Consistent with TMEM216 requirement for primary ciliogenesis in mammalian cells and with the conserved role of worm MKS-2 in sensory (non-motile) cilia. Supporting Evidence: PMID:20512146 Tmem216 knockdown prevented ciliogenesis in polarized cells, and blocked correct docking of centrosomes at the apical cell surface |
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Download this section (compressed HTML)Q: Is TMEM216 a stoichiometric core subunit of the mammalian MKS complex (as MKS-2 is in C. elegans) or a peripheral, substoichiometric member, as suggested by its weak co-purification with TCTN1?
Q: What is the functional relationship between the TMEM216 vesicle pool (with TMEM138/TRAPPII) and its transition-zone pool, i.e. is TMEM216 delivered to the TZ on these vesicles?
Experiment: Generate TMEM216 knockout RPE1 or IMCD3 cells and assess TZ ultrastructure by cryo-ET/EM, TZ recruitment of TMEM67, TCTN1/2, TMEM231 and MKS1 by super-resolution microscopy, and ciliary membrane diffusion by FRAP.
Hypothesis: TMEM216 is required for transition-zone ultrastructure (Y-links/necklace) in mammalian cells, as MKS-module members are in C. elegans.
Type: knockout + ultrastructure/imaging
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