TMEM231 is a conserved two-pass transmembrane protein of the MKS (tectonic) module of the ciliary transition zone, found only in ciliated organisms. It reaches the basal body early in ciliogenesis, before and independently of intraflagellar transport, in a septin-dependent manner, and becomes a biochemical component of the MKS complex with B9D1, B9D2, MKS1, TCTN1-3, CC2D2A and TMEM17. TMEM231 and B9D1 are needed for each other's transition-zone localization and for that of TMEM67 and MKS1, so TMEM231 helps organize the MKS part of the transition zone. Through this it maintains the ciliary diffusion barrier and the ciliary membrane composition (ARL13B, ADCY3, PKD2, INPP5E), supports tissue-dependent ciliogenesis and is required for Sonic hedgehog signalling. Variants cause Joubert syndrome 20, Meckel syndrome 11 and oral-facial-digital syndrome type 3.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid interaction of TMEM231 with KRT31 from the HuRI/proteome-scale interactome map. Reason: Generic protein binding is uninformative. This large-scale Y2H hit with KRT31 (keratin-associated/NOTCH2NL partners are frequent in Y2H screens) has no supporting biological context for a TZ membrane protein. Removal does not assert the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid interaction of TMEM231 with KRT40 from the HuRI/proteome-scale interactome map. Reason: Generic protein binding is uninformative. This large-scale Y2H hit with KRT40 (keratin-associated/NOTCH2NL partners are frequent in Y2H screens) has no supporting biological context for a TZ membrane protein. Removal does not assert the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Binary yeast two-hybrid interaction of TMEM231 with NOTCH2NLA from the HuRI/proteome-scale interactome map. Reason: Generic protein binding is uninformative. This large-scale Y2H hit with NOTCH2NLA (keratin-associated/NOTCH2NL partners are frequent in Y2H screens) has no supporting biological context for a TZ membrane protein. Removal does not assert the interaction is false. |
| GO:0005515 protein binding | IPI PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci... | REMOVE | Summary: High-confidence interaction of TMEM231 with TMEM107 in the study defining TMEM107 as an MKS-module TZ protein. Reason: Generic protein binding is uninformative; the TMEM107 association reflects MKS-module co-membership already captured by the MKS complex annotation. In C. elegans TMEM-107 organizes TMEM-231 recruitment to the TZ. 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:0007224 smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Tmem231 knockout mice have Sonic hedgehog signalling defects. Reason: Hedgehog signalling defects follow from loss of the TZ gate and ciliary membrane composition (e.g. loss of Arl13b, Inpp5e and Smoothened regulation). TMEM231 is not a pathway component per se. Supporting Evidence: PMID:22179047 Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. |
| GO:0007224 smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Tmem231 knockout mice have Sonic hedgehog signalling defects. Reason: Hedgehog signalling defects follow from loss of the TZ gate and ciliary membrane composition (e.g. loss of Arl13b, Inpp5e and Smoothened regulation). TMEM231 is not a pathway component per se. Supporting Evidence: PMID:22179047 Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM231 is a two-pass transmembrane protein. Reason: Correct general location; transition zone/ciliary membrane are informative. Supporting Evidence: PMID:22179047 A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. |
| GO:0032880 regulation of protein localization | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: regulation of protein localization, inherited from the TMEM231 family node. Reason: TMEM231 controls which membrane proteins (Arl13b, Adcy3, Pkd2, Inpp5e) accumulate in cilia and which MKS proteins localize to the TZ. This general term correctly captures its gating role, conserved from worms to mammals. Supporting Evidence: PMID:25869670 For example, Arl13b, Adcy3, Pkd2, and Inpp5e fail to localize to cilia in Tmem231−/− MEFs, and Tmem231 and B9d1 are required for Arl13b ciliary localization in all mouse tissues examined. PMID:25869670 In mice, B9d1 and Tmem231 are required for the TZ localization of each other and their interacting proteins, Tmem67 and Mks1. |
| GO:0035869 ciliary transition zone | IBA GO_REF:0000033 | ACCEPT | Summary: TMEM231 localizes to the ciliary transition zone in mouse cells and tissues and in C. elegans. Reason: Core location, supported by direct localization in MEFs, multiple mouse tissues and worm sensory cilia. Supporting Evidence: PMID:25869670 In wild-type MEFs, Tmem231 and B9d1 are present at the TZ PMID:25869670 Tmem231 and B9d1 localize to the TZ of cilia in the kidney, bile duct, pancreas, trachea, and retina of mice PMID:25869670 Also consistent with a role in the TZ, TMEM-231 localizes specifically to this ciliary region, just distal to the basal body PMID:22179047 The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. file:human/TMEM231/TMEM231-deep-research-falcon.md TMEM231 is a membrane-embedded **organizer of the Meckel-syndrome (MKS) protein module at the ciliary transition zone**. |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM231 localizes to the ciliary transition zone in mouse cells and tissues and in C. elegans. Reason: Core location, supported by direct localization in MEFs, multiple mouse tissues and worm sensory cilia. Supporting Evidence: PMID:25869670 In wild-type MEFs, Tmem231 and B9d1 are present at the TZ PMID:25869670 Tmem231 and B9d1 localize to the TZ of cilia in the kidney, bile duct, pancreas, trachea, and retina of mice PMID:25869670 Also consistent with a role in the TZ, TMEM-231 localizes specifically to this ciliary region, just distal to the basal body PMID:22179047 The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. file:human/TMEM231/TMEM231-deep-research-falcon.md TMEM231 is a membrane-embedded **organizer of the Meckel-syndrome (MKS) protein module at the ciliary transition zone**. |
| GO:0035869 ciliary transition zone | ISS GO_REF:0000024 | ACCEPT | Summary: TMEM231 localizes to the ciliary transition zone in mouse cells and tissues and in C. elegans. Reason: Core location, supported by direct localization in MEFs, multiple mouse tissues and worm sensory cilia. Supporting Evidence: PMID:25869670 In wild-type MEFs, Tmem231 and B9d1 are present at the TZ PMID:25869670 Tmem231 and B9d1 localize to the TZ of cilia in the kidney, bile duct, pancreas, trachea, and retina of mice PMID:25869670 Also consistent with a role in the TZ, TMEM-231 localizes specifically to this ciliary region, just distal to the basal body PMID:22179047 The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. file:human/TMEM231/TMEM231-deep-research-falcon.md TMEM231 is a membrane-embedded **organizer of the Meckel-syndrome (MKS) protein module at the ciliary transition zone**. |
| GO:0035869 ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: TMEM231 localizes to the ciliary transition zone in mouse cells and tissues and in C. elegans. Reason: Core location, supported by direct localization in MEFs, multiple mouse tissues and worm sensory cilia. Supporting Evidence: PMID:25869670 In wild-type MEFs, Tmem231 and B9d1 are present at the TZ PMID:25869670 Tmem231 and B9d1 localize to the TZ of cilia in the kidney, bile duct, pancreas, trachea, and retina of mice PMID:25869670 Also consistent with a role in the TZ, TMEM-231 localizes specifically to this ciliary region, just distal to the basal body PMID:22179047 The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. file:human/TMEM231/TMEM231-deep-research-falcon.md TMEM231 is a membrane-embedded **organizer of the Meckel-syndrome (MKS) protein module at the ciliary transition zone**. |
| GO:0036038 MKS complex | IEA GO_REF:0000107 | ACCEPT | Summary: TMEM231 is a biochemical component of the MKS complex. Reason: LAP-tag purification of Tmem231 recovers B9d1, Mks1, Tctn1-3, Cc2d2a and Tmem17, confirmed by co-IP. Supporting Evidence: PMID:25869670 This experiment confirmed the interaction between B9d1 and Tmem231, and revealed that Tmem231 interacts with multiple other components of the MKS complex, including Mks1, Tctn1, Tctn2, Tctn3, Cc2d2a (Mks6), and Tmem17 PMID:25869670 These data reveal that Tmem231 is a biochemical component of the MKS complex. |
| GO:0036038 MKS complex | ISS GO_REF:0000024 | ACCEPT | Summary: TMEM231 is a biochemical component of the MKS complex. Reason: LAP-tag purification of Tmem231 recovers B9d1, Mks1, Tctn1-3, Cc2d2a and Tmem17, confirmed by co-IP. Supporting Evidence: PMID:25869670 This experiment confirmed the interaction between B9d1 and Tmem231, and revealed that Tmem231 interacts with multiple other components of the MKS complex, including Mks1, Tctn1, Tctn2, Tctn3, Cc2d2a (Mks6), and Tmem17 PMID:25869670 These data reveal that Tmem231 is a biochemical component of the MKS complex. |
| GO:0036038 MKS complex | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: TMEM231 is a biochemical component of the MKS complex. Reason: LAP-tag purification of Tmem231 recovers B9d1, Mks1, Tctn1-3, Cc2d2a and Tmem17, confirmed by co-IP. Supporting Evidence: PMID:25869670 This experiment confirmed the interaction between B9d1 and Tmem231, and revealed that Tmem231 interacts with multiple other components of the MKS complex, including Mks1, Tctn1, Tctn2, Tctn3, Cc2d2a (Mks6), and Tmem17 PMID:25869670 These data reveal that Tmem231 is a biochemical component of the MKS complex. |
| GO:0060170 ciliary membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TMEM231 is a transmembrane protein of the transition-zone portion of the ciliary membrane. Reason: As a two-pass membrane protein localized at the TZ, TMEM231 sits in the ciliary membrane at the ciliary base. Ciliary transition zone is the more specific location. Supporting Evidence: PMID:22179047 A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. PMID:23012439 TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. |
| GO:0060170 ciliary membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TMEM231 is a transmembrane protein of the transition-zone portion of the ciliary membrane. Reason: As a two-pass membrane protein localized at the TZ, TMEM231 sits in the ciliary membrane at the ciliary base. Ciliary transition zone is the more specific location. Supporting Evidence: PMID:22179047 A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. PMID:23012439 TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. |
| GO:0060170 ciliary membrane | ISS GO_REF:0000024 | ACCEPT | Summary: TMEM231 is a transmembrane protein of the transition-zone portion of the ciliary membrane. Reason: As a two-pass membrane protein localized at the TZ, TMEM231 sits in the ciliary membrane at the ciliary base. Ciliary transition zone is the more specific location. Supporting Evidence: PMID:22179047 A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. PMID:23012439 TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Knockdown of the TMEM231/B9D1/CC2D2A complex reduces cilia formation, and mouse knockouts show ciliogenesis defects in some tissues. Tmem231-/- MEFs nonetheless ciliate. Reason: TMEM231 contributes to cilium assembly in a tissue-dependent manner, as for other MKS-module components. Its primary role is building the TZ and controlling ciliary membrane composition. The process annotation is acceptable but should not be read as an absolute requirement for axoneme formation. Supporting Evidence: PMID:22179047 Disruption of the complex in vitro causes a reduction in cilia formation and a loss of signalling receptors from the remaining cilia. PMID:22179047 Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. PMID:25869670 Thus, Tmem231 and B9d1 are essential for controlling the composition of the ciliary membrane, but are not essential for ciliogenesis. |
| GO:0060271 cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Knockdown of the TMEM231/B9D1/CC2D2A complex reduces cilia formation, and mouse knockouts show ciliogenesis defects in some tissues. Tmem231-/- MEFs nonetheless ciliate. Reason: TMEM231 contributes to cilium assembly in a tissue-dependent manner, as for other MKS-module components. Its primary role is building the TZ and controlling ciliary membrane composition. The process annotation is acceptable but should not be read as an absolute requirement for axoneme formation. Supporting Evidence: PMID:22179047 Disruption of the complex in vitro causes a reduction in cilia formation and a loss of signalling receptors from the remaining cilia. PMID:22179047 Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. PMID:25869670 Thus, Tmem231 and B9d1 are essential for controlling the composition of the ciliary membrane, but are not essential for ciliogenesis. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: Knockdown of the TMEM231/B9D1/CC2D2A complex reduces cilia formation, and mouse knockouts show ciliogenesis defects in some tissues. Tmem231-/- MEFs nonetheless ciliate. Reason: TMEM231 contributes to cilium assembly in a tissue-dependent manner, as for other MKS-module components. Its primary role is building the TZ and controlling ciliary membrane composition. The process annotation is acceptable but should not be read as an absolute requirement for axoneme formation. Supporting Evidence: PMID:22179047 Disruption of the complex in vitro causes a reduction in cilia formation and a loss of signalling receptors from the remaining cilia. PMID:22179047 Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. PMID:25869670 Thus, Tmem231 and B9d1 are essential for controlling the composition of the ciliary membrane, but are not essential for ciliogenesis. |
| GO:1904491 protein localization to ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: TMEM231 is required for TZ localization of B9D1, TMEM67 and MKS1, and its TZ localization is interdependent with B9D1 and CC2D2A. Reason: Core process. Directly demonstrated in Tmem231-/- MEFs (with rescue by wild-type but not disease variants) and in the Chih et al. RNAi work. Supporting Evidence: PMID:25869670 In mice, B9d1 and Tmem231 are required for the TZ localization of each other and their interacting proteins, Tmem67 and Mks1. PMID:25869670 In the absence of Tmem231, B9d1 fails to localize to the TZ PMID:22179047 The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. |
| GO:1905349 ciliary transition zone assembly | IMP PMID:25869670 TMEM231, mutated in orofaciodigital and Meckel syndromes, or... | NEW | Summary: Tmem231 is required in mouse cells to assemble the MKS part of the transition zone (TZ localization of B9d1, Tmem67 and Mks1). The paper's own conclusion is that TMEM231 organizes the transition zone. Reason: Participation test: TMEM231 is a structural transmembrane constituent of the TZ MKS module and is required for incorporation of its partners (scaffold case), not merely necessary upstream. GO:1905349 replaces the obsoleted GO:0097711 and is currently annotated to very few genes (CEP290, CCDC66, DZIP1L), so absence for MKS subunits reflects an under-populated term rather than a curation convention. This matches the module's assignment of TZ assembly to the MKS module. Supporting Evidence: PMID:25869670 TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. PMID:25869670 In mice, B9d1 and Tmem231 are required for the TZ localization of each other and their interacting proteins, Tmem67 and Mks1. PMID:25869670 In the absence of Tmem231, B9d1 fails to localize to the TZ |
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Download this section (compressed HTML)Q: Does TMEM231, with septin 2, mark the site of the future transition zone before other MKS components arrive, i.e. is it an early nucleator of MKS-module assembly?
Q: How do disease variants (e.g. those causing OFD3 versus MKS) differ quantitatively in their ability to restore B9D1 recruitment and ARL13B ciliary localization?
Experiment: Live imaging of endogenously tagged TMEM231, B9D1, MKS1 and TCTN2 during serum-starvation-induced ciliogenesis in RPE1 cells, with and without SEPT2 depletion, to order MKS-module arrival at the mother centriole.
Hypothesis: TMEM231 recruitment precedes and templates the MKS module at the ciliary base.
Type: live-cell imaging
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