TMEM43

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005637 nuclear inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: TMEM43/LUMA is predominantly localized to the inner nuclear membrane (INM), as demonstrated through multiple independent studies. The protein requires interaction with A-type lamins for its INM localization and has four transmembrane domains with both termini oriented toward the nucleoplasm [PMID:18230648]. Reason: INM localization is the core subcellular location for TMEM43, well-supported by biochemical and imaging studies. This IBA annotation is phylogenetically sound and consistent with primary literature evidence from PMID:18230648 demonstrating that LUMA is a unique integral inner nuclear membrane protein. Supporting Evidence: PMID:18230648 We present here a first characterization of LUMA, an unique integral inner nuclear membrane (INM) protein. file:human/TMEM43/TMEM43-deep-research-falcon.md model: Edison Scientific Literature
GO:0006629 lipid metabolic process	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: The IBA annotation to lipid metabolic process is propagated from phylogenetic analysis. While TMEM43 localizes to membranes and some studies have linked it to lipid-related pathways in disease contexts (e.g., adipogenic replacement in ARVC), there is no direct experimental evidence that TMEM43 itself functions in lipid metabolism as a core activity. Reason: This annotation appears to be an over-annotation. While ARVC5 caused by TMEM43 mutations involves fibrofatty replacement of cardiomyocytes, this is a disease consequence rather than a direct function of the protein. TMEM43 is a structural membrane protein, not an enzyme or transporter involved in lipid metabolism. The phylogenetic inference may be drawing from indirect associations rather than core molecular function.
GO:0071763 nuclear membrane organization	IBA GO_REF:0000033	ACCEPT	Summary: TMEM43 plays a key role in nuclear membrane organization by maintaining nuclear envelope structure through interactions with emerin, lamins, and SUN2. Mutations disrupt emerin distribution and nuclear envelope integrity [PMID:18230648, PMID:21391237]. Reason: This is a core biological process for TMEM43. The protein is essential for organizing protein complexes at the INM and retaining emerin at its proper location. PMID:18230648 states that LUMA functions as a tetraspanin-like membrane organizer. Supporting Evidence: PMID:18230648 We propose that LUMA functions as a tetraspanin-like membrane organizer and has the potential to contribute to the pathomechanism of dystrophic diseases PMID:21391237 Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei.
GO:0002376 immune system process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: TMEM43 has been shown to modulate innate immune signaling through the cGAS-STING pathway via interaction with RNF26, and plays a role in NF-kappa-B activation downstream of EGFR [PMID:32614325, PMID:27991920]. Reason: The immune-related function is documented but represents a secondary/modulatory role rather than the core function of TMEM43. The protein primarily functions in nuclear envelope organization. PMID:32614325 shows that RNF26 co-assembles with TMEM43 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway. This is valid but not the primary molecular function. Supporting Evidence: PMID:32614325 RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway.
GO:0005637 nuclear inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation for nuclear inner membrane localization is consistent with the IBA annotation and extensive experimental evidence. Reason: Duplicate of the IBA annotation - both correctly reflect the primary subcellular location of TMEM43 at the inner nuclear membrane.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: TMEM43 localizes to the ER membrane in addition to the INM. The protein is initially synthesized in the ER and retained at the INM through interactions with lamins and emerin. The ER and INM are contiguous membrane systems. Reason: ER membrane localization is valid. UniProt explicitly lists Endoplasmic reticulum membrane as a subcellular location. The ER and INM are contiguous, and the protein traffics through the ER. This is a legitimate secondary localization.
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: TMEM43 has been reported at the plasma membrane in specific cell contexts, particularly in cochlear glia-like supporting cells where it contributes to gap junction function [PMID:34050020]. UniProt also lists cell membrane as a subcellular location. Reason: Plasma membrane localization appears to be context-specific, particularly in cochlear cells where TMEM43 interacts with connexins. UniProt lists Cell membrane citing PMID:34050020. This is a valid but secondary localization compared to the primary INM location. Supporting Evidence: PMID:34050020 TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs
GO:0035725 sodium ion transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: This annotation is inferred from the voltage-gated sodium channel activity annotation. However, the ion channel claims for TMEM43 are highly debated. The consensus from recent reviews is that TMEM43 is primarily a structural/adapter protein, not a canonical ion channel. Reason: This is likely an over-annotation. While one preprint suggested voltage-gated channel activity, the broader literature consensus indicates that ion-channel claims for TMEM43 remain debated and tissue-specific, with prevailing data supporting a structural/adapter role. The primary function is nuclear envelope organization, not ion transport.
GO:0045087 innate immune response	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: TMEM43 modulates innate immune signaling through the cGAS-STING pathway via RNF26 interaction, as documented in PMID:32614325. Reason: This is a documented secondary function. TMEM43 does play a role in innate immunity through its interaction with RNF26 and modulation of the cGAS-STING pathway, but this is not its core molecular function. Supporting Evidence: PMID:32614325 RNF26 co-assembles with TMEM43, ENDOD1, TMEM33 and TMED1 to form a complex capable of modulating innate immune signalling through the cGAS-STING pathway.
GO:0071805 potassium ion transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: This annotation is inferred from the voltage-gated potassium channel activity annotation. As noted above, ion channel claims for TMEM43 are debated and not well supported. Reason: Same concern as sodium ion transport annotation. The ion channel function is not the established primary function of TMEM43. While there may be context-specific effects on ion conductance (e.g., in cochlear cells via gap junctions), TMEM43 is not a classical voltage-gated potassium channel.
GO:0098655 monoatomic cation transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Inferred from the voltage-gated cation channel annotation. This suffers from the same issues as the more specific ion transport annotations. Reason: Over-annotation based on disputed ion channel function. TMEM43 is primarily a structural nuclear envelope protein, not a cation transporter.
GO:0005515 protein binding	IPI PMID:21391237 TMEM43 mutations in Emery-Dreifuss muscular dystrophy-relate...	REMOVE	Summary: This annotation comes from a study showing TMEM43 interaction with emerin (EMD/P50402). PMID:21391237 demonstrated that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin. Reason: GO curation guidelines recommend against using the generic protein binding term when more informative terms are available. The specific interaction with emerin and SUN2 should be annotated with more precise terms. The interaction data is valuable but should be captured with terms like lamin binding or specific complex terms. Proposed replacements: lamin binding Supporting Evidence: PMID:21391237 we demonstrated for the first time that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: This annotation is from a large-scale proteome interactome mapping study, not a focused study on TMEM43 function. Reason: Generic protein binding provides no specific functional information. Large-scale interactome studies generate many protein-protein interactions but these should be evaluated for biological relevance and annotated with more specific terms when possible. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	REMOVE	Summary: This annotation is from a study on disease-associated mutation effects on protein interactions, not specific to TMEM43 function. Reason: Generic protein binding without functional context. Should be replaced with more informative terms. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	REMOVE	Summary: From a study on alternative splicing effects on protein interactions. Reason: Generic protein binding is uninformative. High-throughput interaction data should be curated with more specific terms when the interaction has biological significance. Supporting Evidence: PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: From the HuRI human reference interactome mapping study. Multiple interaction partners were identified. Reason: Generic protein binding annotations from large-scale screens do not provide specific functional insight. The specific interactions (e.g., with HTT) might be biologically meaningful but require validation and more specific annotation. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: From a neurodegenerative disease interactome mapping study showing interaction with HTT (huntingtin). Reason: Generic protein binding is uninformative. If the HTT interaction is biologically significant, it should be annotated with a more specific term. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0042802 identical protein binding	IPI PMID:21391237 TMEM43 mutations in Emery-Dreifuss muscular dystrophy-relate...	ACCEPT	Summary: TMEM43 forms homo-oligomers through its transmembrane domains. PMID:18230648 demonstrated that LUMA transmembrane domains also promote homooligomerization and PMID:21391237 confirmed oligomerization capability. Reason: TMEM43 self-oligomerization is a well-documented property important for its function. The protein forms homo-oligomers (dimers, tetramers) mediated by its transmembrane domains. This is functionally relevant as disease mutations (e.g., E85K) can disrupt oligomerization. Supporting Evidence: PMID:18230648 LUMA's transmembrane domains also promote homooligomerization PMID:21391237 p.Glu85Lys mutant LUMA resulted to failure in oligomerization
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000107	ACCEPT	Summary: TMEM43 has a large hydrophilic domain located between transmembrane spans 1 and 2 that is exposed to the perinuclear space (equivalent to ER lumen) [PMID:18230648]. Reason: This is consistent with TMEM43 topology. UniProt notes that the majority of the hydrophilic domain resides in the endoplasmic reticulum lumen. The annotation correctly reflects that part of the protein extends into the ER lumen/perinuclear space. Supporting Evidence: PMID:18230648 The large hydrophilic domain is exposed to the perinuclear space whereas both LUMA termini reside cyto- or nucleoplasmically
GO:0042802 identical protein binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for self-binding, consistent with the IPI evidence from PMID:21391237. Reason: Consistent with experimental evidence for homo-oligomerization.
GO:0005248 voltage-gated sodium channel activity	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: This annotation is from a preprint that claims TMEM43 has voltage-gated sodium channel activity. However, this is highly controversial and not supported by the broader literature. Reason: This is from a preprint (not peer-reviewed) and contradicts the established understanding of TMEM43 as a structural nuclear envelope protein. Ion-channel claims for TMEM43 remain debated and prevailing data support a structural/adapter role. Until peer-reviewed validation is available, this annotation should be treated with caution.
GO:0005249 voltage-gated potassium channel activity	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: Same source as the voltage-gated sodium channel annotation. Subject to the same concerns. Reason: From a preprint with controversial claims not supported by consensus literature. Peer-reviewed validation is needed before accepting this annotation.
GO:0005515 protein binding	IPI DOI:10.1101/2022.11.08.515259	REMOVE	Summary: Protein binding annotation from the same preprint. Reason: Generic protein binding is uninformative regardless of source.
GO:0005886 plasma membrane	IDA DOI:10.1101/2022.11.08.515259	KEEP AS NON CORE	Summary: Plasma membrane localization from the preprint claiming ion channel function. Reason: While the IDA evidence from this preprint should be treated with caution given the controversial claims about channel activity, plasma membrane localization has been documented in other contexts (e.g., cochlear cells, PMID:34050020). Keeping consistent with the IEA annotation for plasma membrane. Supporting Evidence: PMID:34050020 TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs
GO:0006813 potassium ion transport	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: Potassium ion transport annotation from the preprint. Reason: Based on disputed channel activity claims. Requires peer-reviewed validation.
GO:0006814 sodium ion transport	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: Sodium ion transport annotation from the preprint. Reason: Based on disputed channel activity claims. Requires peer-reviewed validation.
GO:0022843 voltage-gated monoatomic cation channel activity	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: Voltage-gated cation channel activity from the preprint. Reason: This represents the central disputed claim of the preprint. While TMEM43 has been grouped with putative channel proteins in some reviews, the consensus is that TMEM43 functions primarily as a structural/adapter protein. Definitive electrophysiology proving intrinsic channel activity in native contexts is lacking.
GO:0030001 metal ion transport	IDA DOI:10.1101/2022.11.08.515259	UNDECIDED	Summary: Metal ion transport annotation from the preprint. Reason: Overly broad term based on disputed channel activity claims. Requires validation.
GO:0071763 nuclear membrane organization	IDA PMID:18230648 LUMA interacts with emerin and influences its distribution a...	ACCEPT	Summary: PMID:18230648 provides direct experimental evidence that TMEM43/LUMA is required for proper organization of the nuclear membrane by maintaining emerin distribution at the INM. Reason: This is the core biological process function of TMEM43, supported by direct experimental evidence. The study demonstrated that LUMA functions as a tetraspanin-like membrane organizer and that manipulation of LUMA levels affects emerin distribution and nuclear envelope structure. Supporting Evidence: PMID:18230648 Both downregulation of LUMA and overexpression of dominant-negative acting LUMA fragments causes redistribution of emerin
GO:0005794 Golgi apparatus	IDA GO_REF:0000054	KEEP AS NON CORE	Summary: Golgi localization from the LIFEdb subcellular localization screen using expressed fusion proteins. Reason: This may represent transient localization during trafficking or a minor pool of the protein. The primary localizations are INM and ER membrane. Golgi localization is not well-supported in the primary literature for TMEM43 function but could be valid for protein trafficking.
GO:0005521 lamin binding	IDA PMID:18230648 LUMA interacts with emerin and influences its distribution a...	NEW	Summary: TMEM43 directly binds A-type and B-type lamins, and this interaction is required for its INM localization. Reason: This is a well-documented molecular function. PMID:18230648 states that LUMA binds lamins and depends on A-type lamins for its INM localization. This is more informative than generic protein binding. Supporting Evidence: PMID:18230648 LUMA binds A- and B-type lamins and depends on A-type lamins for its INM localization.

Gene Description

Existing Annotations Review

Core Functions

TMEM43 functions as a tetraspanin-like membrane organizer at the inner nuclear membrane, maintaining nuclear envelope structure by organizing protein complexes including emerin, lamins, and SUN2. This is the primary biological function.

TMEM43 binds lamins (A-type and B-type) which is required for its retention at the inner nuclear membrane.

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