TARDBP

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003723 RNA binding	IBA GO_REF:0000033	ACCEPT	Summary: RNA binding is the primary molecular function of TDP-43. The protein contains two RRM domains (RRM1/RRM2) that preferentially bind UG-rich RNA motifs, engaging numerous pre-mRNAs and noncoding RNAs (deep research, PMID:11285240). Reason: TDP-43 is a well-characterized RNA-binding protein. The IBA annotation is phylogenetically supported and aligns with extensive experimental evidence from multiple studies demonstrating RNA binding as the core molecular function. Supporting Evidence: PMID:11285240 We have identified TDP-43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG)m sequence. file:human/TARDBP/TARDBP-deep-research-falcon.md model: Edison Scientific Literature
GO:0010468 regulation of gene expression	IBA GO_REF:0000033	ACCEPT	Summary: TDP-43 regulates gene expression through multiple mechanisms including alternative splicing regulation, mRNA stability control, and transcriptional repression (PMID:7745706, PMID:11285240, PMID:18305152). Reason: TDP-43's role in regulating gene expression is well-established through its splicing repressor function, mRNA stability regulation, and transcriptional repression activities. This is a core function of the protein. Supporting Evidence: PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression.
GO:0000785 chromatin	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: TDP-43 has been detected in chromatin fractions and interacts with DNA, though its primary localization and function are in the nucleoplasm for RNA processing. Reason: While TDP-43 can bind DNA and has been detected at chromatin, its primary function is as an RNA-binding protein in the nucleoplasm. The chromatin association is not the core function.
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: TDP-43 is predominantly localized to the nucleoplasm under normal conditions, where it carries out its RNA processing functions (PMID:11285240, PMID:17481916, deep research). Reason: Nuclear/nucleoplasmic localization is well-established for TDP-43 under physiological conditions. Multiple studies confirm this localization. Supporting Evidence: PMID:17481916 In control motor neurons, TDP43 was almost exclusively nuclear
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	ACCEPT	Summary: TDP-43 binds both RNA and DNA, making nucleic acid binding accurate but overly general. Reason: The IEA annotation from InterPro is correct as TDP-43 binds both RNA (UG-rich) and DNA (TG-rich). However, this is subsumed by more specific annotations for RNA binding and DNA binding. Acceptable to keep as it captures the broader function.
GO:0003677 DNA binding	IEA GO_REF:0000043	ACCEPT	Summary: TDP-43 was originally identified as a DNA-binding protein that binds TAR DNA from HIV-1 (PMID:7745706). Reason: DNA binding was demonstrated in the original characterization of TDP-43. While RNA binding is now considered the primary function, DNA binding is experimentally validated. Supporting Evidence: PMID:7745706 We identified a cDNA, designated TAR DNA-binding protein (TDP-43), which encodes a cellular factor of 43 kDa that binds specifically to pyrimidine-rich motifs in TAR.
GO:0003690 double-stranded DNA binding	IEA GO_REF:0000117	ACCEPT	Summary: TDP-43 was shown to bind double-stranded TAR DNA in the original characterization (PMID:7745706). Reason: The original paper demonstrated binding to dsDNA, though primarily to the pyrimidine-rich strand. This annotation is consistent with experimental evidence. Supporting Evidence: PMID:7745706 Although TDP-43 bound strongly to double-stranded TAR DNA via its ribonucleoprotein protein-binding motifs, it did not bind to TAR RNA extending from +1 to +80.
GO:0003723 RNA binding	IEA GO_REF:0000120	ACCEPT	Summary: RNA binding is the primary molecular function of TDP-43. Reason: Duplicate of IBA annotation. RNA binding is TDP-43's core function, supported by extensive experimental evidence. Both IEA and IBA annotations are valid.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: TDP-43 is predominantly localized to the nucleus under normal conditions. Reason: Nuclear localization is well-established for TDP-43. The protein contains a bipartite NLS and is predominantly nuclear in healthy cells.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: TDP-43 can shuttle to the cytoplasm under stress conditions and is found in cytoplasmic aggregates in ALS/FTD pathology. Reason: Cytoplasmic localization is documented, particularly under stress conditions and in disease states. TDP-43 undergoes nucleocytoplasmic shuttling. Supporting Evidence: PMID:17481916 whereas in ALS spinal motor neurons, TDP43 was predominantly localized to the cytosol and not the nucleus
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: TDP-43 has been detected in mitochondria and mitochondrial dysfunction is associated with TDP-43 pathology. Reason: Mitochondrial localization has been reported but is not the primary site of TDP-43 function. Mitochondrial dysfunction is part of disease pathology rather than core function.
GO:0006397 mRNA processing	IEA GO_REF:0000043	ACCEPT	Summary: TDP-43 is directly involved in mRNA processing, particularly alternative splicing (PMID:11285240). Reason: mRNA processing, especially alternative splicing regulation, is a core function of TDP-43. This is well-supported by its role in CFTR exon 9 skipping and cryptic exon repression. Supporting Evidence: PMID:11285240 Transient TDP-43 overexpression in Hep3B cells results in an increase in exon 9 skipping.
GO:0008380 RNA splicing	IEA GO_REF:0000120	ACCEPT	Summary: TDP-43 regulates alternative splicing, particularly through cryptic exon repression (PMID:11285240, deep research). Reason: RNA splicing regulation is a core function of TDP-43. Its role in repressing cryptic exon inclusion is central to disease pathophysiology in ALS/FTD.
GO:0010494 cytoplasmic stress granule	IEA GO_REF:0000044	ACCEPT	Summary: TDP-43 localizes to cytoplasmic stress granules under stress conditions and is involved in stress granule dynamics (deep research). Reason: Stress granule localization is well-documented for TDP-43 and is relevant to its function in RNA metabolism and disease pathophysiology.
GO:0048511 rhythmic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: TDP-43 was shown to interact with CRY1/CRY2 proteins and regulate their stability, thereby affecting circadian period length in cultured cells (PMID:27123980). However, this is not a core function of TDP-43. Reason: While PMID:27123980 demonstrates that TDP-43 stabilizes cryptochrome proteins and knockdown shortens circadian period in cultured cells, this is not a core function. The primary function of TDP-43 is RNA metabolism (splicing, mRNA stability). The circadian effect appears to be a secondary consequence of TDP-43's general role in protein stability regulation rather than a specific circadian function. The deep research on TDP-43 focuses entirely on RNA metabolism and ALS/FTD with no mention of circadian biology as a primary function. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells.
GO:0005515 protein binding	IPI PMID:15231747 A protein interaction framework for human mRNA degradation.	REMOVE	Summary: Generic protein binding annotation from interaction study with Q9H0D6. Reason: Generic protein binding is uninformative for functional annotation. TDP-43 has numerous specific protein interactions that should be captured by more informative terms. Supporting Evidence: PMID:15231747 A protein interaction framework for human mRNA degradation.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	REMOVE	Summary: Generic protein binding annotation from high-throughput interaction study. Reason: Generic protein binding from high-throughput study is not informative. Supporting Evidence: PMID:16169070 A human protein-protein interaction network: a resource for annotating the proteome.
GO:0005515 protein binding	IPI PMID:18377426 Interaction of antiproliferative protein Tob with the CCR4-N...	REMOVE	Summary: Interaction with CCR4-NOT deadenylase complex component (TOB). Reason: Generic protein binding annotation. The interaction with CCR4-NOT complex could be relevant to mRNA stability function but 'protein binding' is too generic. Supporting Evidence: PMID:18377426 Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex.
GO:0005515 protein binding	IPI PMID:20740007 Ataxin-2 intermediate-length polyglutamine expansions are as...	REMOVE	Summary: Interaction with ATXN2 (ataxin-2), relevant to ALS pathogenesis. Reason: While the ATXN2-TDP-43 interaction is disease-relevant, generic 'protein binding' is uninformative. Supporting Evidence: PMID:20740007 Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.
GO:0005515 protein binding	IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ...	REMOVE	Summary: Interaction mapping from innate immunity study. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:21903422 2011 Sep 8. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
GO:0005515 protein binding	IPI PMID:24169621 Elucidating novel hepatitis C virus-host interactions using ...	REMOVE	Summary: HCV-host interaction study. Reason: Generic protein binding from viral-host interaction study is uninformative. Supporting Evidence: PMID:24169621 Epub 2013 Oct 29. Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.
GO:0005515 protein binding	IPI PMID:24690380 Interaction of transactive response DNA binding protein 43 w...	REMOVE	Summary: Interaction with NF-kappaB p65 (RELA). Reason: Generic protein binding. The specific interaction with p65 could be relevant but requires more specific annotation. Supporting Evidence: PMID:24690380 Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits.
GO:0005515 protein binding	IPI PMID:26571498 TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Trans...	REMOVE	Summary: Interaction with importin-alpha showing TDP-43 inhibits NF-kappaB by blocking p65 nuclear translocation. Reason: Generic protein binding. The functional consequence (blocking p65 nuclear translocation) is more informative but not captured by this term. Supporting Evidence: PMID:26571498 eCollection 2015. TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Translocation.
GO:0005515 protein binding	IPI PMID:26752685 FIH Regulates Cellular Metabolism through Hydroxylation of t...	REMOVE	Summary: Interaction with FIH. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:26752685 eCollection 2016 Jan.
GO:0005515 protein binding	IPI PMID:27615052 A novel missense mutation of CMT2P alters transcription mach...	REMOVE	Summary: Interaction with FUS. Reason: Generic protein binding. FUS-TDP-43 interaction is functionally interesting but 'protein binding' is too generic. Supporting Evidence: PMID:27615052 A novel missense mutation of CMT2P alters transcription machinery.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: Human interactome mapping study. Reason: Generic protein binding from interactome study is uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:29109149 Chronic oxidative stress promotes GADD34-mediated phosphoryl...	REMOVE	Summary: Interaction with GADD34 related to TDP-43 phosphorylation under oxidative stress. Reason: Generic protein binding. The functional consequence (phosphorylation) is relevant but not captured by this term. Supporting Evidence: PMID:29109149 2017 Nov 6. Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration.
GO:0005515 protein binding	IPI PMID:29153328 TDP-43 Promotes Neurodegeneration by Impairing Chromatin Rem...	REMOVE	Summary: Interaction with CHD2 (chromatin remodeler). Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:29153328 Epub 2017 Nov 16. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.
GO:0005515 protein binding	IPI PMID:29725819 Senataxin mutations elicit motor neuron degeneration phenoty...	REMOVE	Summary: Interaction with senataxin (SETX). Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:29725819 Epub 2018 May 3. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Large-scale neurodegenerative disease interactome mapping. Reason: Generic protein binding from high-throughput study is uninformative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: OpenCell endogenous tagging study. Reason: Generic protein binding from systematic study is uninformative. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:37788672 Cryo-EM structure of the KLHL22 E3 ligase bound to an oligom...	REMOVE	Summary: Interaction with KLHL22 E3 ligase. Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:37788672 Epub 2023 Oct 2. Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme.
GO:0042802 identical protein binding	IPI PMID:19383787 Aberrant cleavage of TDP-43 enhances aggregation and cellula...	ACCEPT	Summary: TDP-43 self-association is critical for both function and pathological aggregation. The N-terminal domain oligomerization supports splicing function while aberrant aggregation is pathological (PMID:19383787, deep research). Reason: TDP-43 self-association/oligomerization is functionally important for its splicing activity and is central to understanding ALS/FTD pathology. This is more informative than generic protein binding. Supporting Evidence: PMID:19383787 we report that the ectopic expression of a approximately 25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions
GO:0042802 identical protein binding	IPI PMID:21666678 An ALS-associated mutation affecting TDP-43 enhances protein...	ACCEPT	Summary: ALS mutation enhances TDP-43 self-association and aggregation. Reason: Confirms self-association relevant to both function and disease. Supporting Evidence: PMID:21666678 An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity.
GO:0042802 identical protein binding	IPI PMID:22193716 Redox signalling directly regulates TDP-43 via cysteine oxid...	ACCEPT	Summary: Redox regulation of TDP-43 via cysteine oxidation affects self-association. Reason: Demonstrates regulation of TDP-43 self-association, relevant to function. Supporting Evidence: PMID:22193716 Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking.
GO:0042802 identical protein binding	IPI PMID:23384725 Molecular mechanism of oxidation-induced TDP-43 RRM1 aggrega...	ACCEPT	Summary: Oxidation-induced TDP-43 RRM1 aggregation and loss of function. Reason: Documents self-association mechanism. Supporting Evidence: PMID:23384725 2013 Feb 4. Molecular mechanism of oxidation-induced TDP-43 RRM1 aggregation and loss of function.
GO:0042802 identical protein binding	IPI PMID:26099433 TDP-35 sequesters TDP-43 into cytoplasmic inclusions through...	ACCEPT	Summary: TDP-35 (truncated form) sequesters full-length TDP-43 via self-association. Reason: Relevant to understanding aggregation pathology. Supporting Evidence: PMID:26099433 2015 Jun 19. TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA.
GO:0042802 identical protein binding	IPI PMID:26735904 ALS-Causing Mutations Significantly Perturb the Self-Assembl...	ACCEPT	Summary: ALS mutations perturb self-assembly of the prion-like domain (PMID:26735904). Reason: Self-association via the C-terminal domain is critical for phase separation and pathological aggregation. Supporting Evidence: PMID:26735904 eCollection 2016 Jan.
GO:0042802 identical protein binding	IPI PMID:29531287 Atomic-level evidence for packing and positional amyloid pol...	ACCEPT	Summary: Structural analysis of TDP-43 amyloid polymorphism. Reason: Supports self-association in amyloid formation. Supporting Evidence: PMID:29531287 Epub 2018 Mar 12. Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2.
GO:0042802 identical protein binding	IPI PMID:31235914 Cryo-EM structures of four polymorphic TDP-43 amyloid cores.	ACCEPT	Summary: Cryo-EM structures of TDP-43 amyloid cores. Reason: Structural evidence for self-association in amyloid formation. Supporting Evidence: PMID:31235914 Epub 2019 Jun 24. Cryo-EM structures of four polymorphic TDP-43 amyloid cores.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: Transferred from mouse ortholog. TDP-43 was originally identified binding to TAR DNA element in HIV-1 promoter region and can repress transcription (PMID:7745706). Reason: Consistent with the original characterization showing TDP-43 binds TAR DNA and represses transcription. The promoter-proximal binding activity is documented. Supporting Evidence: PMID:7745706 TDP-43 repressed in vitro transcription from the HIV-1 long terminal repeat in both the presence and absence of Tat, but it did not repress transcription from other promoters
GO:0005726 perichromatin fibrils	IEA GO_REF:0000107	ACCEPT	Summary: Transferred from rat ortholog. Perichromatin fibrils are sites of nascent transcript processing, consistent with TDP-43's RNA processing function. Reason: Consistent with TDP-43's role in co-transcriptional RNA processing.
GO:0016607 nuclear speck	IEA GO_REF:0000107	ACCEPT	Summary: Transferred from rat ortholog. Nuclear speckles are enriched in splicing factors. Reason: Consistent with TDP-43's role as a splicing regulator.
GO:0031647 regulation of protein stability	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: TDP-43 regulates protein stability of target proteins including CRY1/CRY2 (PMID:27123980). Reason: While TDP-43 can affect protein stability (e.g., cryptochrome proteins), this is not its core function. Its primary role is in RNA metabolism.
GO:0032024 positive regulation of insulin secretion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Transferred from rat ortholog. This is likely a downstream consequence rather than direct function. Reason: Not a core function of TDP-43. The deep research and literature focus entirely on RNA metabolism and neurodegeneration with no mention of insulin secretion as a primary function.
GO:0034976 response to endoplasmic reticulum stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ER stress is associated with TDP-43 pathology. Reason: ER stress is part of the pathological response in TDP-43 proteinopathies but is not a core physiological function.
GO:0035061 interchromatin granule	IEA GO_REF:0000107	ACCEPT	Summary: Transferred from rat. Interchromatin granules are equivalent to nuclear speckles. Reason: Consistent with TDP-43's nuclear localization and RNA processing function.
GO:0042307 positive regulation of protein import into nucleus	IEA GO_REF:0000107	UNDECIDED	Summary: Transferred from mouse ortholog. Reason: Cannot verify this function from available literature. The referenced mouse study is not available for review.
GO:0042752 regulation of circadian rhythm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: TDP-43 was shown to regulate circadian period through stabilization of CRY proteins (PMID:27123980). Reason: While there is experimental evidence from PMID:27123980 that TDP-43 stabilizes CRY proteins and knockdown shortens circadian period in cultured cells, this is not a core function. The extensive literature on TDP-43 focuses on RNA metabolism and neurodegeneration. The circadian effect appears to be a secondary consequence of TDP-43's broader role in protein stability rather than a specific circadian function. Supporting Evidence: PMID:27123980 We found that Tdp-43 knockdown shortened the circadian period (Fig 6A)
GO:0097157 pre-mRNA intronic binding	IEA GO_REF:0000107	ACCEPT	Summary: TDP-43 binds UG-rich intronic sequences to regulate splicing (PMID:11285240). Reason: TDP-43 binds to (UG)n repeats in introns to regulate splicing, as demonstrated for CFTR exon 9. This is a core function. Supporting Evidence: PMID:11285240 Several studies have identified in the IVS8 intron 3' splice site a regulatory element that is composed of a polymorphic (TG)m(T)n repeated sequence.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence data showing nucleoplasmic localization. Reason: Nucleoplasm is the primary localization of TDP-43 under normal conditions.
GO:0003677 DNA binding	EXP PMID:26735904 ALS-Causing Mutations Significantly Perturb the Self-Assembl...	ACCEPT	Summary: Experimental demonstration of DNA binding by the prion-like domain of TDP-43. Reason: DNA binding is documented, consistent with original characterization. Supporting Evidence: PMID:26735904 eCollection 2016 Jan.
GO:0008289 lipid binding	EXP PMID:26735904 ALS-Causing Mutations Significantly Perturb the Self-Assembl...	KEEP AS NON CORE	Summary: The prion-like domain of TDP-43 shows lipid binding activity. Reason: Lipid binding by the disordered C-terminal domain is documented but not a core function. May be relevant to membrane interactions during phase separation. Supporting Evidence: PMID:26735904 eCollection 2016 Jan.
GO:0140693 molecular condensate scaffold activity	IDA PMID:27545621 ALS Mutations Disrupt Phase Separation Mediated by α-Helical...	ACCEPT	Summary: TDP-43 undergoes liquid-liquid phase separation mediated by its alpha-helical C-terminal domain. ALS mutations disrupt this phase separation. Reason: Phase separation/condensate formation is central to TDP-43 function and dysfunction. Multiple studies demonstrate this activity. Supporting Evidence: PMID:27545621 Aug 18. ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain.
GO:0140693 molecular condensate scaffold activity	IDA PMID:28988034 The physical forces mediating self-association and phase-sep...	ACCEPT	Summary: Physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43. Reason: Additional support for phase separation activity. Supporting Evidence: PMID:28988034 The physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43.
GO:0140693 molecular condensate scaffold activity	IDA PMID:29511089 TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase sepa...	ACCEPT	Summary: TDP-43 liquid-liquid phase separation is mediated by aromatic residues. Reason: Further mechanistic support for phase separation. Supporting Evidence: PMID:29511089 Epub 2018 Mar 6. TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues.
GO:1990000 amyloid fibril formation	IDA PMID:26735904 ALS-Causing Mutations Significantly Perturb the Self-Assembl...	ACCEPT	Summary: TDP-43 can form amyloid fibrils, particularly the C-terminal fragments found in disease inclusions. Reason: Amyloid fibril formation is documented for TDP-43, particularly relevant to disease pathology. While pathological, it reflects an intrinsic property of the protein. Supporting Evidence: PMID:26735904 eCollection 2016 Jan.
GO:0003723 RNA binding	IMP PMID:25678563 Peptidylprolyl isomerase A governs TARDBP function and assem...	ACCEPT	Summary: PPIA (cyclophilin A) regulates TDP-43 function and assembly in hnRNP complexes. TDP-43 RNA binding function is demonstrated. Reason: Additional experimental support for RNA binding. Supporting Evidence: PMID:25678563 PPIA regulates expression of known TARDBP RNA targets and is necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein complexes.
GO:0005515 protein binding	IPI PMID:25678563 Peptidylprolyl isomerase A governs TARDBP function and assem...	REMOVE	Summary: Interaction with PPIA (cyclophilin A). Reason: Generic protein binding is uninformative. The specific interaction with PPIA is functionally relevant but not captured by this generic term. Supporting Evidence: PMID:25678563 Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes.
GO:0005634 nucleus	IDA PMID:25678563 Peptidylprolyl isomerase A governs TARDBP function and assem...	ACCEPT	Summary: Nuclear localization demonstrated. Reason: Confirms nuclear localization. Supporting Evidence: PMID:25678563 Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes.
GO:0031647 regulation of protein stability	IMP PMID:27123980 USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Prot...	KEEP AS NON CORE	Summary: TDP-43 regulates stability of CRY proteins, affecting circadian period. Reason: TDP-43 affects CRY protein stability but this is not its core function. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2
GO:0061158 3'-UTR-mediated mRNA destabilization	IDA PMID:28335005 TDP-43 suppresses tau expression via promoting its mRNA inst...	ACCEPT	Summary: TDP-43 promotes tau mRNA instability via 3'-UTR binding. Reason: mRNA stability regulation via 3'-UTR binding is a core function of TDP-43. Supporting Evidence: PMID:28335005 TDP-43 suppresses tau expression via promoting its mRNA instability.
GO:0005515 protein binding	IPI PMID:23541532 Ubiquilin-2 (UBQLN2) binds with high affinity to the C-termi...	REMOVE	Summary: Interaction with UBQLN2 (ubiquilin-2). Reason: Generic protein binding is uninformative. Supporting Evidence: PMID:23541532 Ubiquilin-2 (UBQLN2) binds with high affinity to the C-terminal region of TDP-43 and modulates TDP-43 levels in H4 cells: characterization of inhibition by nucleic acids and 4-aminoquinolines.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	ACCEPT	Summary: High-throughput RNA-binding proteome study. Reason: Additional support for RNA binding from systematic study. Supporting Evidence: PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	ACCEPT	Summary: mRNA-bound proteome study. Reason: Additional support for RNA binding. Supporting Evidence: PMID:22681889 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
GO:0001933 negative regulation of protein phosphorylation	IMP PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation thro...	KEEP AS NON CORE	Summary: TDP-43 represses CDK6 expression, leading to reduced pRb phosphorylation (PMID:18305152). Reason: This is a downstream consequence of TDP-43's transcriptional/splicing regulation rather than a direct phosphatase or kinase regulator function. Supporting Evidence: PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels... Cdk6 up-regulation in TDP-43-depleted cells is accompanied by an increase in phosphorylation of two of its major targets
GO:0010629 negative regulation of gene expression	IMP PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation thro...	ACCEPT	Summary: TDP-43 represses CDK6 expression (PMID:18305152). Reason: Transcriptional repression is a documented function of TDP-43. Supporting Evidence: PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. The control of Cdk6 expression mediated by TDP-43 involves GT repeats in the target gene sequence.
GO:0042981 regulation of apoptotic process	IMP PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation thro...	KEEP AS NON CORE	Summary: TDP-43 depletion leads to apoptosis via the pRb pathway (PMID:18305152). Reason: Apoptosis regulation is a downstream consequence of TDP-43 depletion affecting CDK6-pRb pathway, not a direct apoptosis regulatory function. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis
GO:0051726 regulation of cell cycle	IMP PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation thro...	KEEP AS NON CORE	Summary: TDP-43 affects cell cycle through CDK6-pRb pathway regulation (PMID:18305152). Reason: Cell cycle effects are downstream of TDP-43's primary gene expression regulatory function, not a direct cell cycle role. Supporting Evidence: PMID:18305152 loss of TDP-43 results in... misregulation of the cell cycle
GO:0071765 nuclear inner membrane organization	IMP PMID:18305152 TDP-43 regulates retinoblastoma protein phosphorylation thro...	KEEP AS NON CORE	Summary: TDP-43 depletion causes dysmorphic nuclear shape (PMID:18305152). Reason: Nuclear morphology effects are a downstream consequence of TDP-43 depletion, not a direct membrane organization function. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape
GO:0005634 nucleus	IDA GO_REF:0000054	ACCEPT	Summary: Nuclear localization from fusion protein imaging. Reason: Confirms nuclear localization.
GO:0003690 double-stranded DNA binding	IDA PMID:7745706 Cloning and characterization of a novel cellular protein, TD...	ACCEPT	Summary: Original characterization showed TDP-43 binds to double-stranded TAR DNA. Reason: Direct experimental evidence from the original cloning paper. Supporting Evidence: PMID:7745706 Although TDP-43 bound strongly to double-stranded TAR DNA via its ribonucleoprotein protein-binding motifs, it did not bind to TAR RNA extending from +1 to +80.
GO:0003723 RNA binding	IDA PMID:11285240 Nuclear factor TDP-43 and SR proteins promote in vitro and i...	ACCEPT	Summary: Demonstrated TDP-43 binds to (TG)m sequences (RNA) regulating CFTR exon 9 splicing. Reason: Landmark paper establishing TDP-43 as an RNA-binding protein affecting splicing. Supporting Evidence: PMID:11285240 We have identified TDP-43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG)m sequence.
GO:0003730 mRNA 3'-UTR binding	IDA PMID:17481916 TDP43 is a human low molecular weight neurofilament (hNFL) m...	ACCEPT	Summary: TDP-43 binds to the 3'-UTR of neurofilament light (NFL) mRNA, stabilizing it (PMID:17481916). Reason: 3'-UTR binding is a well-characterized function of TDP-43 involved in mRNA stability regulation and autoregulation. Supporting Evidence: PMID:17481916 We observed that TDP43 stabilizes the human low molecular weight (hNFL) mRNA through a direct interaction with the 3'UTR.
GO:0005634 nucleus	IDA PMID:11285240 Nuclear factor TDP-43 and SR proteins promote in vitro and i...	ACCEPT	Summary: Nuclear localization demonstrated. Reason: Confirms nuclear localization. Supporting Evidence: PMID:11285240 Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.
GO:0005634 nucleus	IDA PMID:17481916 TDP43 is a human low molecular weight neurofilament (hNFL) m...	ACCEPT	Summary: Nuclear localization in control motor neurons. Reason: Confirms nuclear localization under normal conditions. Supporting Evidence: PMID:17481916 In control motor neurons, TDP43 was almost exclusively nuclear
GO:0008380 RNA splicing	IDA PMID:11285240 Nuclear factor TDP-43 and SR proteins promote in vitro and i...	ACCEPT	Summary: TDP-43 regulates CFTR exon 9 splicing (PMID:11285240). Reason: RNA splicing regulation is a core function of TDP-43, demonstrated for CFTR and many other transcripts. Supporting Evidence: PMID:11285240 Transient TDP-43 overexpression in Hep3B cells results in an increase in exon 9 skipping. This effect is more pronounced with concomitant overexpression of SR proteins.
GO:0043922 host-mediated suppression of viral transcription	IDA PMID:7745706 Cloning and characterization of a novel cellular protein, TD...	ACCEPT	Summary: TDP-43 represses HIV-1 gene expression by binding TAR DNA (PMID:7745706). Reason: While discovered in context of HIV, this reflects TDP-43's transcriptional repressor activity and is the original functional characterization. Supporting Evidence: PMID:7745706 TDP-43 repressed in vitro transcription from the HIV-1 long terminal repeat in both the presence and absence of Tat... transfection of a vector which expressed TDP-43 resulted in the repression of gene expression from an HIV-1 provirus.
GO:0070935 3'-UTR-mediated mRNA stabilization	IDA PMID:17481916 TDP43 is a human low molecular weight neurofilament (hNFL) m...	ACCEPT	Summary: TDP-43 stabilizes NFL mRNA through 3'-UTR binding (PMID:17481916). Reason: mRNA stabilization through 3'-UTR binding is a core function of TDP-43. Supporting Evidence: PMID:17481916 We observed that TDP43 stabilizes the human low molecular weight (hNFL) mRNA through a direct interaction with the 3'UTR.

Gene Description

Existing Annotations Review

Core Functions

TDP-43 binds UG-rich RNA sequences via its two RRM domains. This is the primary molecular function enabling its roles in splicing, mRNA stability, and transport.

TDP-43 binds 3'-UTR sequences to regulate mRNA stability, including autoregulation of its own mRNA and stabilization of neurofilament mRNA. This supports its role in splicing regulation and cryptic exon repression.

TDP-43 undergoes liquid-liquid phase separation via its C-terminal low-complexity domain, forming nuclear condensates that support function and stress granules under stress conditions.

References

Deep Research

Falcon

📚 Additional Documentation

Bioreason Rl Predictions

Bioreason Rl Review

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