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 Oxidation-induced TDP-43 RRM1 aggregation and loss of functi...	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.

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.

Molecular Function:

RNA binding

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.

Molecular Function:

mRNA 3'-UTR binding

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.

Molecular Function:

molecular condensate scaffold activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000054

Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:7745706

Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs.

Original identification of TDP-43 as a DNA-binding protein
Binds pyrimidine-rich motifs in TAR DNA
Represses HIV-1 transcription

PMID:11285240

Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.

First demonstration of TDP-43 RNA binding
Binds (TG)m sequences to regulate splicing
Promotes CFTR exon 9 skipping

PMID:17481916

TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein.

TDP-43 stabilizes NFL mRNA via 3'-UTR binding
Nuclear in control motor neurons, cytoplasmic in ALS

PMID:18305152

TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression.

TDP-43 represses CDK6 expression
Depletion causes nuclear defects, cell cycle problems, and apoptosis

PMID:19383787

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity.

C-terminal fragments form toxic aggregates
25-kDa fragment specific to pathological inclusions

PMID:25678563

Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes.

PPIA regulates TDP-43 function and hnRNP assembly

PMID:27123980

USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Protein Stability Paces the Oscillation of the Mammalian Circadian Clock.

TDP-43 stabilizes CRY1 and CRY2 proteins
Knockdown shortens circadian period in cultured cells
Effect is FBXL3-dependent

PMID:27545621

ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain.

Phase separation mediated by C-terminal domain
ALS mutations disrupt phase separation

PMID:28988034

The physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43.

Biophysical characterization of phase separation

PMID:29511089

TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues.

Aromatic residues critical for phase separation

PMID:15231747

A protein interaction framework for human mRNA degradation.

PMID:16169070

A human protein-protein interaction network: a resource for annotating the proteome.

PMID:18377426

Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex.

PMID:20740007

Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.

PMID:21903422

Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

PMID:24169621

Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.

PMID:24690380

Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits.

PMID:26571498

TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Translocation.

PMID:26752685

FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.

PMID:27615052

A novel missense mutation of CMT2P alters transcription machinery.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29109149

Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration.

PMID:29153328

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.

PMID:29725819

Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:37788672

Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme.

PMID:21666678

An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity.

PMID:22193716

Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking.

PMID:23384725

Oxidation-induced TDP-43 RRM1 aggregation and loss of function.

PMID:26099433

TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA.

PMID:26735904

ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43.

ALS mutations affect prion-like domain self-assembly
DNA and lipid binding demonstrated

PMID:29531287

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2.

PMID:31235914

Cryo-EM structures of four polymorphic TDP-43 amyloid cores.

PMID:28335005

TDP-43 suppresses tau expression via promoting its mRNA instability.

TDP-43 destabilizes tau mRNA through 3-UTR binding

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.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

file:human/TARDBP/TARDBP-deep-research-falcon.md

Deep research report on TARDBP

📚 Additional Documentation

Deep Research Bioreason

(TARDBP-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:44 AM

Organism: Homo sapiens

Sequence:

MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the polypeptide. The N-terminus carries IPR041105 (TAR DNA-binding protein 43, N-terminal domain, residues 4–77), a hallmark oligomerization and nucleic-acid engagement module that seeds assembly of higher-order ribonucleoprotein complexes. Mid-protein, a continuous nucleic-acid–handling core is evident: IPR012677 (Nucleotide-binding alpha-beta plait domain superfamily, residues 90–269) and IPR000504 (RNA recognition motif domain, residues 104–262) overlap extensively, establishing a canonical RRM fold that binds single-stranded RNA with sequence and structure selectivity. This core is further reinforced by IPR035979 (RNA-binding domain superfamily, residues 106–293), which generalizes the RNA-binding capability and indicates broad affinity for structured and repetitive RNA motifs. The C-terminus transitions into IPR049124 (TAR DNA-binding protein 43, C-terminal domain, residues 262–371), a region known to stabilize trimeric assemblies and tune nucleic-acid affinity and partner selection. The linear arrangement—N-terminal oligomerization domain → central RRM-based nucleic-acid binding core → C-terminal assembly/stability module—creates a modular platform that causes high-avidity RNA recognition and multivalent ribonucleoprotein formation.

From this architecture, the molecular function resolves as nucleic-acid binding with a bias toward RNA. The RRM and RNA-binding superfamily signatures (IPR000504, IPR012677, IPR035979) specify primary chemistry as RNA recognition and assembly of RNA-containing complexes, which corresponds to GO:0003723 RNA binding. The N-terminal and C-terminal trimerization/stability domains (IPR041105 and IPR049124) amplify this function by producing cooperative binding that supports both RNA chaperoning and ribosome-associated RNA handling.

These binding activities naturally extend to RNA metabolism. By engaging and stabilizing specific RNA elements, the protein modulates RNA fate—splicing, transport, stability, and translation—which maps to GO:0016071 RNA metabolic process. The explicit association with translating assemblies implied by the RRM core and the trimerizing termini supports involvement in protein synthesis pathways, consistent with GO:0006412 translation. Together, these processes arise causally from the domain architecture that builds dynamic ribonucleoprotein assemblies.

Cellular location follows from assembly behavior and trafficking cues. The presence of nucleic-acid–binding modules without signal peptides or transmembrane segments argues for a soluble, non-membranous protein that shuttles between compartments. Its capacity to form cytoplasmic RNPs and ribosome-associated complexes supports a cytoplasmic residency, while its participation in RNA maturation pathways and nucleocytoplasmic shuttling supports a nuclear pool. This reasoning supports GO:0005737 cytoplasm and GO:0005634 nucleus, aligning with dual localization.

Mechanistically, the N-terminal trimerization domain nucleates higher-order assemblies; the central RRM core confers sequence/structure-selective RNA binding; and the C-terminal domain stabilizes complexes and tunes nucleic-acid affinity. This architecture causes avid binding to structured and repetitive RNA motifs and drives formation of cytoplasmic RNPs that associate with ribosomes. I therefore hypothesize interactions with cytoplasmic ribosomes and translation factors, with nuclear export/import machinery that mediates shuttling, and with other RNA-binding proteins that co-assemble into ribonucleoprotein granules. Likely partners include ribosomal subunits and initiation/elongation factors in the cytoplasm, spliceosomal and hnRNP components in the nucleus, and transport receptors that coordinate nucleocytoplasmic trafficking. These assemblies collectively position the protein as a hub that couples RNA recognition to translational and post-transcriptional regulation across nucleus and cytoplasm.

Functional Summary

A soluble nucleic-acid–binding protein that assembles into higher-order ribonucleoprotein complexes to regulate RNA fate. Its N-terminal oligomerization module and a central RNA-recognition core cooperate with a stabilizing C-terminus to bind and chaperone structured RNAs, thereby coordinating post-transcriptional events such as processing, transport, stability, and translation. The assemblies it forms operate in both nucleus and cytoplasm and likely couple RNA recognition to ribosome-associated functions.

UniProt Summary

DNA-binding protein.

InterPro Domains

TAR DNA-binding protein 43, N-terminal (IPR041105, domain) — residues 4-77
Nucleotide-binding alpha-beta plait domain superfamily (IPR012677, homologous_superfamily) — residues 90-269
RNA recognition motif domain (IPR000504, domain) — residues 104-262
RNA-binding domain superfamily (IPR035979, homologous_superfamily) — residues 106-293
TAR DNA-binding protein 43, C-terminal (IPR049124, domain) — residues 262-371

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), molecular adaptor activity (GO:0060090), heterocyclic compound binding (GO:1901363), lipid binding (GO:0008289), protein-macromolecule adaptor activity (GO:0030674), organic cyclic compound binding (GO:0097159), protein binding (GO:0005515), nucleic acid binding (GO:0003676), molecular condensate scaffold activity (GO:0140693), identical protein binding (GO:0042802), DNA binding (GO:0003677), RNA binding (GO:0003723), double-stranded DNA binding (GO:0003690), mRNA binding (GO:0003729), mRNA 3'-UTR binding (GO:0003730)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), biological process involved in interspecies interaction between organisms (GO:0044419), biological regulation (GO:0065007), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), regulation of metabolic process (GO:0019222), nitrogen compound metabolic process (GO:0006807), cellular component organization or biogenesis (GO:0071840), organic substance metabolic process (GO:0071704), biological process involved in symbiotic interaction (GO:0044403), negative regulation of metabolic process (GO:0009892), regulation of biological quality (GO:0065008), cellular metabolic process (GO:0044237), positive regulation of cellular process (GO:0048522), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), negative regulation of cellular process (GO:0048523), primary metabolic process (GO:0044238), negative regulation of nitrogen compound metabolic process (GO:0051172), regulation of RNA stability (GO:0043487), organonitrogen compound metabolic process (GO:1901564), positive regulation of macromolecule metabolic process (GO:0010604), heterocycle metabolic process (GO:0046483), biological process involved in interaction with symbiont (GO:0051702), protein metabolic process (GO:0019538), regulation of macromolecule metabolic process (GO:0060255), cellular aromatic compound metabolic process (GO:0006725), cellular nitrogen compound metabolic process (GO:0034641), regulation of protein stability (GO:0031647), negative regulation of cellular metabolic process (GO:0031324), macromolecule metabolic process (GO:0043170), regulation of cell cycle (GO:0051726), regulation of catabolic process (GO:0009894), organic cyclic compound metabolic process (GO:1901360), regulation of cell death (GO:0010941), nucleobase-containing compound metabolic process (GO:0006139), positive regulation of cellular metabolic process (GO:0031325), negative regulation of macromolecule metabolic process (GO:0010605), regulation of biosynthetic process (GO:0009889), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cellular metabolic process (GO:0031323), cellular component organization (GO:0016043), negative regulation of biosynthetic process (GO:0009890), negative regulation of catabolic process (GO:0009895), regulation of primary metabolic process (GO:0080090), positive regulation of catabolic process (GO:0009896), positive regulation of nitrogen compound metabolic process (GO:0051173), regulation of macromolecule biosynthetic process (GO:0010556), regulation of protein metabolic process (GO:0051246), endomembrane system organization (GO:0010256), regulation of programmed cell death (GO:0043067), regulation of mRNA stability (GO:0043488), negative regulation of cellular catabolic process (GO:0031330), negative regulation of protein metabolic process (GO:0051248), positive regulation of gene expression (GO:0010628), RNA destabilization (GO:0050779), amyloid fibril formation (GO:1990000), regulation of gene expression (GO:0010468), modulation by host of symbiont process (GO:0051851), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), regulation of amide metabolic process (GO:0034248), nucleic acid metabolic process (GO:0090304), RNA stabilization (GO:0043489), regulation of cellular biosynthetic process (GO:0031326), negative regulation of phosphorus metabolic process (GO:0010563), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive regulation of cellular catabolic process (GO:0031331), negative regulation of macromolecule biosynthetic process (GO:0010558), negative regulation of cellular biosynthetic process (GO:0031327), regulation of RNA metabolic process (GO:0051252), regulation of cellular catabolic process (GO:0031329), organelle organization (GO:0006996), negative regulation of RNA metabolic process (GO:0051253), gene expression (GO:0010467), negative regulation of gene expression (GO:0010629), regulation of phosphorus metabolic process (GO:0051174), supramolecular fiber organization (GO:0097435), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), negative regulation of amide metabolic process (GO:0034249), membrane organization (GO:0061024), negative regulation of mRNA catabolic process (GO:1902373), negative regulation of translation (GO:0017148), regulation of apoptotic process (GO:0042981), RNA metabolic process (GO:0016070), regulation of mRNA catabolic process (GO:0061013), regulation of protein modification process (GO:0031399), negative regulation of mRNA metabolic process (GO:1903312), negative regulation of protein modification process (GO:0031400), positive regulation of mRNA catabolic process (GO:0061014), nuclear envelope organization (GO:0006998), RNA processing (GO:0006396), negative regulation of RNA catabolic process (GO:1902369), regulation of phosphate metabolic process (GO:0019220), nuclear membrane organization (GO:0071763), mRNA stabilization (GO:0048255), nucleus organization (GO:0006997), regulation of cellular macromolecule biosynthetic process (GO:2000112), regulation of translation (GO:0006417), mRNA destabilization (GO:0061157), regulation of mRNA metabolic process (GO:1903311), negative regulation of cellular macromolecule biosynthetic process (GO:2000113), negative regulation of phosphate metabolic process (GO:0045936), positive regulation of mRNA metabolic process (GO:1903313), post-transcriptional regulation of gene expression (GO:0010608), regulation of phosphorylation (GO:0042325), negative regulation of protein phosphorylation (GO:0001933), regulation of protein phosphorylation (GO:0001932), negative regulation of phosphorylation (GO:0042326), RNA splicing (GO:0008380), 3'-UTR-mediated mRNA stabilization (GO:0070935), 3'-UTR-mediated mRNA destabilization (GO:0061158)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane-enclosed lumen (GO:0031974), nucleoplasm (GO:0005654), organelle lumen (GO:0043233), intracellular organelle (GO:0043229), membrane-bounded organelle (GO:0043227), non-membrane-bounded organelle (GO:0043228), intracellular membrane-bounded organelle (GO:0043231), intracellular organelle lumen (GO:0070013), intracellular non-membrane-bounded organelle (GO:0043232), nuclear lumen (GO:0031981), nucleus (GO:0005634)

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Deep Research Bioreason Rl

(TARDBP-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:44 AM

Organism: Homo sapiens

Sequence:

MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM

Thinking Trace

Functional Summary

UniProt Summary

DNA-binding protein.

InterPro Domains

TAR DNA-binding protein 43, N-terminal (IPR041105, domain) — residues 4-77
Nucleotide-binding alpha-beta plait domain superfamily (IPR012677, homologous_superfamily) — residues 90-269
RNA recognition motif domain (IPR000504, domain) — residues 104-262
RNA-binding domain superfamily (IPR035979, homologous_superfamily) — residues 106-293
TAR DNA-binding protein 43, C-terminal (IPR049124, domain) — residues 262-371

GO Terms

Generated by BioReason

Deep Research Falcon

(TARDBP-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-01-18T20:51:05.091985'
end_time: '2026-01-18T20:55:23.817392'
duration_seconds: 258.73
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: TARDBP
gene_symbol: TARDBP
uniprot_accession: Q13148
protein_description: 'RecName: Full=TAR DNA-binding protein 43 {ECO:0000303|PubMed:7745706};
Short=TDP-43 {ECO:0000303|PubMed:7745706};'
gene_info: Name=TARDBP {ECO:0000303|PubMed:18396105, ECO:0000312|HGNC:HGNC:11571};
Synonyms=TDP43 {ECO:0000303|PubMed:7745706};
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: Nucleotide-bd_a/b_plait_sf. (IPR012677); RBD_domain_sf. (IPR035979);
RRM_dom. (IPR000504); TDP-43_C. (IPR049124); TDP-43_N. (IPR041105)
provider_config:
timeout: 600
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citation_count: 18

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13148
Protein Description: RecName: Full=TAR DNA-binding protein 43 {ECO:0000303|PubMed:7745706}; Short=TDP-43 {ECO:0000303|PubMed:7745706};
Gene Information: Name=TARDBP {ECO:0000303|PubMed:18396105, ECO:0000312|HGNC:HGNC:11571}; Synonyms=TDP43 {ECO:0000303|PubMed:7745706};
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: Nucleotide-bd_a/b_plait_sf. (IPR012677); RBD_domain_sf. (IPR035979); RRM_dom. (IPR000504); TDP-43_C. (IPR049124); TDP-43_N. (IPR041105)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "TARDBP" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'TARDBP' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene TARDBP (gene ID: TARDBP, UniProt: Q13148) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13148
Protein Description: RecName: Full=TAR DNA-binding protein 43 {ECO:0000303|PubMed:7745706}; Short=TDP-43 {ECO:0000303|PubMed:7745706};
Gene Information: Name=TARDBP {ECO:0000303|PubMed:18396105, ECO:0000312|HGNC:HGNC:11571}; Synonyms=TDP43 {ECO:0000303|PubMed:7745706};
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: Nucleotide-bd_a/b_plait_sf. (IPR012677); RBD_domain_sf. (IPR035979); RRM_dom. (IPR000504); TDP-43_C. (IPR049124); TDP-43_N. (IPR041105)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "TARDBP" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene TARDBP (gene ID: TARDBP, UniProt: Q13148) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research plan and verification
We verified the identity of the target as human TARDBP (UniProt Q13148), encoding TAR DNA-binding protein 43 (TDP-43), a 414-amino-acid RNA/DNA-binding hnRNP with an N-terminal domain containing a bipartite nuclear localization signal (NLS), two RNA-recognition motifs (RRM1/RRM2), and a glycine-rich, low-complexity C-terminal domain (LCD). TDP-43 is predominantly nuclear but shuttles to the cytoplasm and localizes to stress granules; it binds UG-rich RNA and TG-rich ssDNA and is dosage-sensitive and essential. These features match the UniProt context and recent literature (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58, part2024exploringtherole pages 26-30, riemenschneider2024exploringcellulartoxicity pages 24-27).

1) Key concepts and definitions
- Gene/protein: TARDBP (chromosome 1p36.22) encodes TDP-43, a ubiquitous RNA-binding protein central to RNA metabolism. Domain architecture: NTD with bipartite NLS (~aa 82–98), RRM1/RRM2 for nucleic acid binding, and a prion-like LCD/CTD harboring most ALS/FTD mutations and driving phase separation and aggregation (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58, part2024exploringtherole pages 26-30, riemenschneider2024exploringcellulartoxicity pages 24-27).
- Nucleic-acid specificity: TDP-43 preferentially binds UGn-enriched RNAs and TG-rich ssDNA, engaging numerous pre-mRNAs and noncoding RNAs (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58).
- Primary molecular functions: repression of cryptic exon inclusion and alternative splicing; regulation of mRNA stability and transport (including axonal); participation in miRNA biogenesis; autoregulation by binding its own 3′UTR to adjust TARDBP mRNA levels (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58, part2024exploringtherole pages 26-30).
- Localization: predominantly nuclear; nucleocytoplasmic shuttling via NLS and reported NES; recruitment to stress granules and other RNP condensates under stress; nuclear TDP-43 condensation supports function (lepine2024theeffectsof pages 54-58, part2024exploringtherole pages 26-30).

2) Recent developments and latest research (prioritized 2023–2024)
- Pathogenesis scope: TDP-43 proteinopathy—nuclear depletion with cytoplasmic mislocalization and aggregation—is present in ~95–97% of ALS cases and ~45–>50% of FTLD cases, implicating combined loss- and gain-of-function mechanisms (Sep 4, 2023; Neural Regeneration Research; https://doi.org/10.4103/1673-5374.382233) (wang2024thepathogenicmechanism pages 1-1). 2024 reviews further synthesize mechanisms spanning nucleocytoplasmic transport, RNA metabolism, stress granules/LLPS, mitochondrial/ER dysfunction, proteostasis, and DNA damage responses (2024; dissertations/reviews) (riemenschneider2024exploringcellulartoxicity pages 24-27).
- LLPS/aggregation and oligomerization: N-terminal oligomerization supports splicing and LLPS; monomerization predisposes to pathology, linking early conformational states to disease (Science Advances, Aug 2023; https://doi.org/10.1126/sciadv.adf6895) (not in context ids). Reviews in 2024 detail LLPS control by domains and RNA (riemenschneider2024exploringcellulartoxicity pages 24-27).
- Autoregulation and dosage: TDP-43 tightly autoregulates via 3′UTR binding; shortened cytosolic isoforms (sTDP-43) arise as byproducts of autoregulation and are normally cleared by NMD and post-translational degradation; overexpression or escape from surveillance can be toxic (bioRxiv, Jul 2, 2024; https://doi.org/10.1101/2024.07.02.601776) (wang2024thepathogenicmechanism pages 1-1, lepine2024theeffectsof pages 54-58).
- RNA chaperone therapeutics: Short UG-containing RNAs can chaperone TDP-43 into soluble, import-competent conformers in cells and mouse models, improving phenotypes, whereas pure UG-repeats can disrupt function; motif design is critical (bioRxiv, Dec 14, 2024; https://doi.org/10.1101/2024.12.14.628507) (copley2024shortrnachaperones pages 15-17).
- Small-molecule-guided transcriptome correction: Connectivity Map-guided screen in TDP-43 mutant iPSC motor neurons identified MLN4924 (NAE inhibitor) as restoring viability and activity, implicating NEDDylation pathways (Scientific Reports preprint, Dec 2024; https://doi.org/10.21203/rs.3.rs-5404388/v1) (lepine2024transcriptomebasedscreeningin pages 49-54).

3) Current applications and real-world implementations
- Biomarkers: Neurofilament light (NfL) is widely used as a fluid biomarker reflecting axonal injury in ALS/FTD though not specific to TDP-43; pathological TDP-43 species in tissue remain a post-mortem diagnostic gold standard (2024) (part2024exploringtherole pages 26-30).
- RNA therapeutics: ASO strategies correcting cryptic splicing downstream of TDP-43 loss-of-function (e.g., STMN2 and UNC13A) are a leading translational direction; platform learnings from SOD1-ASO approvals inform TDP-43–centric programs (2023–2024 reviews cited within the context) (wang2024thepathogenicmechanism pages 1-1, lepine2024transcriptomebasedscreeningin pages 49-54).
- Experimental RNA chaperones: Short RNAs designed to bind RRMs can mitigate aggregation and improve motor neuron outcomes in preclinical models, suggesting a feasible modality akin to ASOs (Dec 2024) (copley2024shortrnachaperones pages 15-17).

4) Expert opinions and analyses
- Recent reviews emphasize that TDP-43’s disease contribution integrates loss-of-function (cryptic exon derepression and splicing failure) with toxic gain-of-function (cytoplasmic condensates/aggregates), and that perturbations in nucleocytoplasmic transport, SG dynamics/LLPS, mitochondrial and ER-Golgi homeostasis intersect with RNA metabolism defects (Sep 2023; Neural Regeneration Research; 2024 dissertations/reviews) (wang2024thepathogenicmechanism pages 1-1, riemenschneider2024exploringcellulartoxicity pages 24-27).

5) Relevant statistics and data
- Prevalence in ALS: TDP-43 pathology in ~95–97% of ALS autopsies; familial ALS 5–10% of total; TARDBP mutations contribute ~4% of fALS, <1% of sALS (Sep 2023; Neural Regeneration Research; https://doi.org/10.4103/1673-5374.382233) (wang2024thepathogenicmechanism pages 1-1).
- Structural mutation distribution: Most ALS/FTD-linked TARDBP missense mutations map to the glycine-rich CTD/LCD, consistent with LLPS/aggregation roles (2024) (casiraghi2024aggregationmechanismsof pages 10-14, part2024exploringtherole pages 26-30).

Detailed functional annotation of TDP-43
- Binding specificity and targets: TDP-43 binds UGn-rich motifs across pre-mRNAs and ncRNAs; it represses cryptic exon inclusion in transcripts such as STMN2 and UNC13A, and regulates POLDIP3 and many neuronal RNAs implicated in axonal health (2024) (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58).
- Autoregulation: TDP-43 binds a conserved region in its 3′UTR (TDPBR) to downregulate its own mRNA; dosage sensitivity is reinforced by NMD of shortened transcripts and rapid degradation of truncated protein products (Jul 2024) (lepine2024theeffectsof pages 54-58, wang2024thepathogenicmechanism pages 1-1).
- Subcellular localization and trafficking: Nuclear predominance via NLS; shuttling to cytoplasm under stress; incorporation into stress granules and other condensates. Nuclear condensation is linked to function; chronic stress/defective resolution predisposes to cytoplasmic aggregation (2024) (lepine2024theeffectsof pages 54-58, part2024exploringtherole pages 26-30, riemenschneider2024exploringcellulartoxicity pages 24-27).
- Phase separation/aggregation: LLPS is driven by multivalent RNA interactions (RRMs) and LCD interactions; persistent droplets can mature to less dynamic gels/solids. NTD oligomerization is essential for normal function; destabilization/monomerization increases aggregation propensity (2023–2024) (riemenschneider2024exploringcellulartoxicity pages 24-27).
- Post-translational modifications (PTMs): Pathological inclusions contain hyperphosphorylated (S409/S410 and S403/S404), ubiquitinated, and C-terminally cleaved TDP-43; SUMOylation and acetylation have been reported, and PTMs modulate LLPS and aggregation dynamics (2024) (part2024exploringtherole pages 26-30).

Pathways and cellular processes
- RNA surveillance and UPF1/NMD: TDP-43 interfaces with RNA surveillance and NMD; TDP-43 dysfunction perturbs UPF1-dependent RNA metabolism and alternative polyadenylation in disease models (2024 overview and related sources within context) (wang2024thepathogenicmechanism pages 1-1).
- Autophagy/UPS: Proteostasis pathways (ubiquitin–proteasome and autophagy) are consistently implicated in handling TDP-43 and its fragments; dysregulation contributes to accumulation and toxicity (2024) (wang2024thepathogenicmechanism pages 1-1, part2024exploringtherole pages 26-30).
- DNA damage response and nuclear bodies: TDP-43 interacts with lncRNA NEAT1 and paraspeckle biology; nuclear condensate homeostasis and DNA repair pathways are increasingly linked to TDP-43 function and dysfunction (2024 context) (riemenschneider2024exploringcellulartoxicity pages 24-27).
- Organelle trafficking: Mitochondrial and ER/secretory pathway disturbances co-occur with TDP-43 pathology; stress granule persistence and defective clearance connect to neurite/axonal transport defects (2023–2024 reviews) (wang2024thepathogenicmechanism pages 1-1, riemenschneider2024exploringcellulartoxicity pages 24-27).

Disease associations and clinical context
- ALS/FTD: Central to ALS (~95–97% pathology) and a major subset of FTLD; both wild-type and mutant TDP-43 contribute. TARDBP mutations are relatively rare causes but highlight critical structure–function links (wang2024thepathogenicmechanism pages 1-1, lepine2024transcriptomebasedscreeningin pages 49-54).
- LATE and AD co-pathology: TDP-43 proteinopathy appears in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frequently co-occurs with AD, compounding neurotoxicity (2024 overview) (part2024exploringtherole pages 26-30, wang2024thepathogenicmechanism pages 1-1).

Therapeutic directions under active investigation
- ASOs restoring downstream targets: Strategies restoring STMN2 and other critical transcripts misprocessed upon TDP-43 loss-of-function are advancing preclinically (2023–2024 reviews summarized in context) (wang2024thepathogenicmechanism pages 1-1).
- Precision expression systems: Conceptual platforms exploit TDP-43 loss-of-function–triggered cryptic splicing to gate therapeutic expression selectively in diseased neurons (“TDP-REG”-like approaches), aligning with the principle of disease-restricted activation (2024 concept referenced in overviews) (wang2024thepathogenicmechanism pages 1-1).
- RNA chaperone/oligonucleotide binders: Carefully designed GU-rich RNAs (non–pure GU repeats) that bind RRMs can keep TDP-43 soluble and nuclear without impairing cryptic exon repression, showing efficacy in cell and mouse models (Dec 2024; bioRxiv) (copley2024shortrnachaperones pages 15-17).
- Small molecules: Pathway-guided screens (e.g., MLN4924) and proteostasis modulators are being explored to rebalance TDP-43 homeostasis (Dec 2024) (lepine2024transcriptomebasedscreeningin pages 49-54).
- Antibodies and immunotherapies: Considered for extracellular/propagating species or to modulate intracellular pools, but translational hurdles remain (2024 review perspective) (riemenschneider2024exploringcellulartoxicity pages 24-27).

Conclusion
Human TARDBP/TDP-43 (UniProt Q13148) is a dosage-sensitive, essential RBP with well-defined domains and UG-rich RNA specificity, orchestrating splicing repression (including cryptic exon suppression), mRNA stability/transport, and tight autoregulation via its 3′UTR. It is predominantly nuclear and undergoes regulated nucleocytoplasmic shuttling and LLPS; disease involves nuclear loss with cytoplasmic aggregation harboring hallmark PTMs. TDP-43 proteinopathy is nearly universal in ALS and prevalent in FTLD and aging-related TDP-43 encephalopathy, with multisystem cellular disturbances converging on RNA metabolism, proteostasis, organelle function, and nuclear body dynamics. 2023–2024 work refines early pathogenic steps (oligomerization/monomerization balance, nuclear condensation), expands links to RNA surveillance and organelle traffic, and advances oligonucleotide-based modalities (ASOs and RNA chaperones) and small-molecule strategies toward restoring TDP-43 homeostasis and downstream transcript integrity (casiraghi2024aggregationmechanismsof pages 10-14, lepine2024theeffectsof pages 54-58, lepine2024transcriptomebasedscreeningin pages 49-54, wang2024thepathogenicmechanism pages 1-1, part2024exploringtherole pages 26-30, riemenschneider2024exploringcellulartoxicity pages 24-27, copley2024shortrnachaperones pages 15-17, lepine2024theeffectsof pages 49-54).

References

(casiraghi2024aggregationmechanismsof pages 10-14): V Casiraghi. Aggregation mechanisms of tdp-43 protein in response to stress in amyotrophic lateral sclerosis and therapeutic approaches. Unknown journal, 2024.
(lepine2024theeffectsof pages 54-58): S Lépine. The effects of tardbp mutations associated with amyotrophic lateral sclerosis in human motor neurons derived from induced pluripotent stem cells. Unknown journal, 2024.
(part2024exploringtherole pages 26-30): Caroline Part. Exploring the role of endogenous tdp-43 sumoylation in mice: implications for amyotrophic lateral sclerosis and frontotemporal dementia. Text, Feb 2024. URL: https://doi.org/10.20381/ruor-30175, doi:10.20381/ruor-30175. This article has 0 citations and is from a peer-reviewed journal.
(riemenschneider2024exploringcellulartoxicity pages 24-27): Henrick Riemenschneider. Exploring cellular toxicity mechanisms and immunotherapeutic potential of tdp-43 in als/ftd. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.34109, doi:10.5282/edoc.34109. This article has 0 citations.
(wang2024thepathogenicmechanism pages 1-1): Xinxin Wang, Yushu Hu, and Renshi Xu. The pathogenic mechanism of tar dna-binding protein 43 (tdp-43) in amyotrophic lateral sclerosis. Neural Regeneration Research, 19:800-806, Sep 2024. URL: https://doi.org/10.4103/1673-5374.382233, doi:10.4103/1673-5374.382233. This article has 29 citations and is from a peer-reviewed journal.
(copley2024shortrnachaperones pages 15-17): Katie E. Copley, Jocelyn C. Mauna, Helen Danielson, Marilyn Ngo, Longxin Xie, Ashleigh Smirnov, Matt Davis, Leland Mayne, Miriam Linsenmeier, Jack D. Rubien, Bede Portz, Bo Lim Lee, Hana M. Odeh, Martina Hallegger, Jernej Ule, Piera Pasinelli, Yan Poon, Nicolas L. Fawzi, Ben E. Black, Christopher J. Donnelly, Brigid K. Jensen, and James Shorter. Short rna chaperones promote aggregation-resistant tdp-43 conformers to mitigate neurodegeneration. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2024.12.14.628507, doi:10.1101/2024.12.14.628507. This article has 4 citations and is from a poor quality or predatory journal.
(lepine2024transcriptomebasedscreeningin pages 49-54): Sarah Lépine, Gilles Maussion, Alexandria Schneider, Angela Nauleau-Javaudin, María José Castellanos-Montiel, Georgina Jiménez Ambriz, Dan Spiegelman, Narges Abdian, Anna Krystina Franco-Flores, Ghazal Haghi, Lale Gursu, Mathilde Chaineau, and Thomas Durcan. Transcriptome-based screening in tardbp/tdp-43 knock-in motor neurons identifies the nedd8-activating enzyme inhibitor mln4924. Scientific Reports, Dec 2024. URL: https://doi.org/10.21203/rs.3.rs-5404388/v1, doi:10.21203/rs.3.rs-5404388/v1. This article has 1 citations and is from a peer-reviewed journal.
(lepine2024theeffectsof pages 49-54): S Lépine. The effects of tardbp mutations associated with amyotrophic lateral sclerosis in human motor neurons derived from induced pluripotent stem cells. Unknown journal, 2024.

Citations

wang2024thepathogenicmechanism pages 1-1
riemenschneider2024exploringcellulartoxicity pages 24-27
copley2024shortrnachaperones pages 15-17
lepine2024transcriptomebasedscreeningin pages 49-54
part2024exploringtherole pages 26-30
casiraghi2024aggregationmechanismsof pages 10-14
lepine2024theeffectsof pages 54-58
lepine2024theeffectsof pages 49-54
https://doi.org/10.4103/1673-5374.382233
https://doi.org/10.1126/sciadv.adf6895
https://doi.org/10.1101/2024.07.02.601776
https://doi.org/10.1101/2024.12.14.628507
https://doi.org/10.21203/rs.3.rs-5404388/v1
https://doi.org/10.20381/ruor-30175,
https://doi.org/10.5282/edoc.34109,
https://doi.org/10.4103/1673-5374.382233,
https://doi.org/10.1101/2024.12.14.628507,
https://doi.org/10.21203/rs.3.rs-5404388/v1,

Bioreason Rl Review

(TARDBP-bioreason-rl-review.md)

BioReason-Pro RL Review: TARDBP (human)

Source: TARDBP-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 3/5

Functional Summary Review

The BioReason functional summary states:

A soluble nucleic-acid-binding protein that assembles into higher-order ribonucleoprotein complexes to regulate RNA fate. Its N-terminal oligomerization module and a central RNA-recognition core cooperate with a stabilizing C-terminus to bind and chaperone structured RNAs, thereby coordinating post-transcriptional events such as processing, transport, stability, and translation. The assemblies it forms operate in both nucleus and cytoplasm and likely couple RNA recognition to ribosome-associated functions.

This captures the core features of TDP-43 (TARDBP) reasonably well. The curated review describes it as "a highly conserved, dosage-sensitive RNA-binding protein essential for RNA metabolism" with RRM domains that bind UG-rich RNA and TG-rich DNA. BioReason correctly identifies:

RNA binding (GO:0003723) via RRM domains
N-terminal oligomerization domain
Nuclear and cytoplasmic distribution
Roles in RNA processing, transport, stability
Higher-order RNP complex formation

However, there are notable gaps and inaccuracies:

DNA binding omitted: TDP-43 was originally identified as a TAR DNA-binding protein. The curated review includes DNA binding (GO:0003677) as a function. While RNA binding is the dominant function, the DNA-binding capacity is part of the gene's identity.
Splicing function underemphasized: TDP-43's role as a splicing regulator is its best-characterized nuclear function, including regulation of cryptic exon inclusion (particularly the STMN2 cryptic exon in neurodegeneration). BioReason mentions "processing" generically but does not highlight splicing.
The C-terminal low-complexity domain (prion-like domain) and its role in liquid-liquid phase separation and pathological aggregation are not mentioned. This is a defining feature of TDP-43 biology.
Translation role: BioReason claims involvement in "translation" and "ribosome-associated functions," which is speculative. TDP-43's role in translation is less well-established compared to its splicing and mRNA stability functions.

Comparison with interpro2go:

The interpro2go annotations from IPR000504 (RRM domain) would map to RNA binding and nucleic acid binding. BioReason recapitulates this and adds the N-terminal and C-terminal TDP-43-specific domain context. The predicted GO terms include mRNA binding (GO:0003729) and mRNA 3'-UTR binding (GO:0003730), which are accurate and present in the curated review. BioReason modestly extends beyond interpro2go by incorporating TDP-43-specific domain architecture.

Notes on thinking trace

The trace correctly identifies the N-terminal domain (IPR041105), RRM domain, and C-terminal domain (IPR049124). The description of the C-terminus as a "stabilizing" module underrepresents its role as a disordered, aggregation-prone region. The mechanistic hypothesis about ribosomal interactions is speculative.

📄 View Raw YAML

id: Q13148
gene_symbol: TARDBP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TDP-43 (TAR DNA-binding protein 43) is a highly conserved, dosage-sensitive RNA-binding
  protein
  essential for RNA metabolism. It contains an N-terminal domain with a bipartite
  nuclear localization
  signal (NLS), two RNA recognition motifs (RRM1/RRM2) that bind UG-rich RNA and TG-rich
  ssDNA, and
  a glycine-rich C-terminal low-complexity domain (LCD) that mediates phase separation
  and harbors
  most ALS/FTD-associated mutations. TDP-43's core functions include: (1) repression
  of cryptic exon
  inclusion in pre-mRNAs such as STMN2 and UNC13A, (2) regulation of mRNA stability
  and transport
  including axonal transport of neurofilament mRNA, (3) autoregulation of its own
  mRNA levels via
  3'-UTR binding, and (4) participation in stress granule dynamics through liquid-liquid
  phase
  separation. TDP-43 is predominantly nuclear but shuttles to the cytoplasm under
  stress. TDP-43
  proteinopathy (nuclear depletion with cytoplasmic mislocalization and aggregation
  containing
  hyperphosphorylated, ubiquitinated, and C-terminally cleaved TDP-43) is present
  in 95-97% of ALS
  cases and approximately 45-50% of FTLD cases.
existing_annotations:
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: "We have identified TDP-43, a nuclear protein not previously
            described to bind RNA, as the factor binding specifically to the (TG)m
            sequence."
        - reference_id: file:human/TARDBP/TARDBP-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "TDP-43 regulates retinoblastoma protein phosphorylation
            through the repression of cyclin-dependent kinase 6 expression."
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      reason: >-
        Nuclear/nucleoplasmic localization is well-established for TDP-43 under physiological
        conditions.
        Multiple studies confirm this localization.
      supported_by:
        - reference_id: PMID:17481916
          supporting_text: "In control motor neurons, TDP43 was almost exclusively
            nuclear"
  - term:
      id: GO:0003676
      label: nucleic acid binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        TDP-43 binds both RNA and DNA, making nucleic acid binding accurate but overly
        general.
      action: ACCEPT
      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.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        TDP-43 was originally identified as a DNA-binding protein that binds TAR DNA
        from HIV-1
        (PMID:7745706).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7745706
          supporting_text: "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."
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        TDP-43 was shown to bind double-stranded TAR DNA in the original characterization
        (PMID:7745706).
      action: ACCEPT
      reason: >-
        The original paper demonstrated binding to dsDNA, though primarily to the
        pyrimidine-rich
        strand. This annotation is consistent with experimental evidence.
      supported_by:
        - reference_id: PMID:7745706
          supporting_text: "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."
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        RNA binding is the primary molecular function of TDP-43.
      action: ACCEPT
      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.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        TDP-43 is predominantly localized to the nucleus under normal conditions.
      action: ACCEPT
      reason: >-
        Nuclear localization is well-established for TDP-43. The protein contains
        a bipartite NLS
        and is predominantly nuclear in healthy cells.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        TDP-43 can shuttle to the cytoplasm under stress conditions and is found in
        cytoplasmic
        aggregates in ALS/FTD pathology.
      action: ACCEPT
      reason: >-
        Cytoplasmic localization is documented, particularly under stress conditions
        and in disease
        states. TDP-43 undergoes nucleocytoplasmic shuttling.
      supported_by:
        - reference_id: PMID:17481916
          supporting_text: "whereas in ALS spinal motor neurons, TDP43 was predominantly
            localized to the cytosol and not the nucleus"
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        TDP-43 has been detected in mitochondria and mitochondrial dysfunction is
        associated with
        TDP-43 pathology.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0006397
      label: mRNA processing
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        TDP-43 is directly involved in mRNA processing, particularly alternative splicing
        (PMID:11285240).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: "Transient TDP-43 overexpression in Hep3B cells results
            in an increase in exon 9 skipping."
  - term:
      id: GO:0008380
      label: RNA splicing
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        TDP-43 regulates alternative splicing, particularly through cryptic exon repression
        (PMID:11285240, deep research).
      action: ACCEPT
      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.
  - term:
      id: GO:0010494
      label: cytoplasmic stress granule
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        TDP-43 localizes to cytoplasmic stress granules under stress conditions and
        is involved
        in stress granule dynamics (deep research).
      action: ACCEPT
      reason: >-
        Stress granule localization is well-documented for TDP-43 and is relevant
        to its function
        in RNA metabolism and disease pathophysiology.
  - term:
      id: GO:0048511
      label: rhythmic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      additional_reference_ids:
        - PMID:27123980
      supported_by:
        - reference_id: PMID:27123980
          supporting_text: "TDP-43 stabilized CRY1 and CRY2, and its knockdown also
            shortened the circadian period in cultured cells."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15231747
    review:
      summary: >-
        Generic protein binding annotation from interaction study with Q9H0D6.
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative for functional annotation. TDP-43
        has numerous
        specific protein interactions that should be captured by more informative
        terms.
      supported_by:
        - reference_id: PMID:15231747
          supporting_text: A protein interaction framework for human mRNA 
            degradation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    review:
      summary: >-
        Generic protein binding annotation from high-throughput interaction study.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study is not informative.
      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource
            for annotating the proteome.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18377426
    review:
      summary: >-
        Interaction with CCR4-NOT deadenylase complex component (TOB).
      action: REMOVE
      reason: >-
        Generic protein binding annotation. The interaction with CCR4-NOT complex
        could be
        relevant to mRNA stability function but 'protein binding' is too generic.
      supported_by:
        - reference_id: PMID:18377426
          supporting_text: Interaction of antiproliferative protein Tob with the
            CCR4-NOT deadenylase complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20740007
    review:
      summary: >-
        Interaction with ATXN2 (ataxin-2), relevant to ALS pathogenesis.
      action: REMOVE
      reason: >-
        While the ATXN2-TDP-43 interaction is disease-relevant, generic 'protein binding'
        is
        uninformative.
      supported_by:
        - reference_id: PMID:20740007
          supporting_text: Ataxin-2 intermediate-length polyglutamine expansions
            are associated with increased risk for ALS.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21903422
    review:
      summary: >-
        Interaction mapping from innate immunity study.
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:21903422
          supporting_text: 2011 Sep 8. Mapping a dynamic innate immunity protein
            interaction network regulating type I interferon production.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24169621
    review:
      summary: >-
        HCV-host interaction study.
      action: REMOVE
      reason: >-
        Generic protein binding from viral-host interaction study is uninformative.
      supported_by:
        - reference_id: PMID:24169621
          supporting_text: Epub 2013 Oct 29. Elucidating novel hepatitis C 
            virus-host interactions using combined mass spectrometry and 
            functional genomics approaches.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24690380
    review:
      summary: >-
        Interaction with NF-kappaB p65 (RELA).
      action: REMOVE
      reason: >-
        Generic protein binding. The specific interaction with p65 could be relevant
        but
        requires more specific annotation.
      supported_by:
        - reference_id: PMID:24690380
          supporting_text: Interaction of transactive response DNA binding 
            protein 43 with nuclear factor κB in mild cognitive impairment with 
            episodic memory deficits.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26571498
    review:
      summary: >-
        Interaction with importin-alpha showing TDP-43 inhibits NF-kappaB by blocking
        p65
        nuclear translocation.
      action: REMOVE
      reason: >-
        Generic protein binding. The functional consequence (blocking p65 nuclear
        translocation)
        is more informative but not captured by this term.
      supported_by:
        - reference_id: PMID:26571498
          supporting_text: eCollection 2015. TDP-43 Inhibits NF-κB Activity by 
            Blocking p65 Nuclear Translocation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26752685
    review:
      summary: >-
        Interaction with FIH.
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:26752685
          supporting_text: eCollection 2016 Jan.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27615052
    review:
      summary: >-
        Interaction with FUS.
      action: REMOVE
      reason: >-
        Generic protein binding. FUS-TDP-43 interaction is functionally interesting
        but
        'protein binding' is too generic.
      supported_by:
        - reference_id: PMID:27615052
          supporting_text: A novel missense mutation of CMT2P alters 
            transcription machinery.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        Human interactome mapping study.
      action: REMOVE
      reason: >-
        Generic protein binding from interactome study is uninformative.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29109149
    review:
      summary: >-
        Interaction with GADD34 related to TDP-43 phosphorylation under oxidative
        stress.
      action: REMOVE
      reason: >-
        Generic protein binding. The functional consequence (phosphorylation) is relevant
        but not captured by this term.
      supported_by:
        - reference_id: PMID:29109149
          supporting_text: 2017 Nov 6. Chronic oxidative stress promotes 
            GADD34-mediated phosphorylation of the TAR DNA-binding protein 
            TDP-43, a modification linked to neurodegeneration.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29153328
    review:
      summary: >-
        Interaction with CHD2 (chromatin remodeler).
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:29153328
          supporting_text: Epub 2017 Nov 16. TDP-43 Promotes Neurodegeneration 
            by Impairing Chromatin Remodeling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29725819
    review:
      summary: >-
        Interaction with senataxin (SETX).
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:29725819
          supporting_text: Epub 2018 May 3. Senataxin mutations elicit motor 
            neuron degeneration phenotypes and yield TDP-43 mislocalization in 
            ALS4 mice and human patients.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        Large-scale neurodegenerative disease interactome mapping.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study is uninformative.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging study.
      action: REMOVE
      reason: >-
        Generic protein binding from systematic study is uninformative.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37788672
    review:
      summary: >-
        Interaction with KLHL22 E3 ligase.
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:37788672
          supporting_text: Epub 2023 Oct 2. Cryo-EM structure of the KLHL22 E3 
            ligase bound to an oligomeric metabolic enzyme.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:19383787
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:19383787
          supporting_text: "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"
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21666678
    review:
      summary: >-
        ALS mutation enhances TDP-43 self-association and aggregation.
      action: ACCEPT
      reason: >-
        Confirms self-association relevant to both function and disease.
      supported_by:
        - reference_id: PMID:21666678
          supporting_text: An ALS-associated mutation affecting TDP-43 enhances 
            protein aggregation, fibril formation and neurotoxicity.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:22193716
    review:
      summary: >-
        Redox regulation of TDP-43 via cysteine oxidation affects self-association.
      action: ACCEPT
      reason: >-
        Demonstrates regulation of TDP-43 self-association, relevant to function.
      supported_by:
        - reference_id: PMID:22193716
          supporting_text: Redox signalling directly regulates TDP-43 via 
            cysteine oxidation and disulphide cross-linking.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23384725
    review:
      summary: >-
        Oxidation-induced TDP-43 RRM1 aggregation and loss of function.
      action: ACCEPT
      reason: >-
        Documents self-association mechanism.
      supported_by:
        - reference_id: PMID:23384725
          supporting_text: 2013 Feb 4. Molecular mechanism of oxidation-induced 
            TDP-43 RRM1 aggregation and loss of function.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:26099433
    review:
      summary: >-
        TDP-35 (truncated form) sequesters full-length TDP-43 via self-association.
      action: ACCEPT
      reason: >-
        Relevant to understanding aggregation pathology.
      supported_by:
        - reference_id: PMID:26099433
          supporting_text: 2015 Jun 19. TDP-35 sequesters TDP-43 into 
            cytoplasmic inclusions through binding with RNA.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:26735904
    review:
      summary: >-
        ALS mutations perturb self-assembly of the prion-like domain (PMID:26735904).
      action: ACCEPT
      reason: >-
        Self-association via the C-terminal domain is critical for phase separation
        and
        pathological aggregation.
      supported_by:
        - reference_id: PMID:26735904
          supporting_text: eCollection 2016 Jan.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:29531287
    review:
      summary: >-
        Structural analysis of TDP-43 amyloid polymorphism.
      action: ACCEPT
      reason: >-
        Supports self-association in amyloid formation.
      supported_by:
        - reference_id: PMID:29531287
          supporting_text: Epub 2018 Mar 12. Atomic-level evidence for packing 
            and positional amyloid polymorphism by segment from TDP-43 RRM2.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:31235914
    review:
      summary: >-
        Cryo-EM structures of TDP-43 amyloid cores.
      action: ACCEPT
      reason: >-
        Structural evidence for self-association in amyloid formation.
      supported_by:
        - reference_id: PMID:31235914
          supporting_text: Epub 2019 Jun 24. Cryo-EM structures of four 
            polymorphic TDP-43 amyloid cores.
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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).
      action: ACCEPT
      reason: >-
        Consistent with the original characterization showing TDP-43 binds TAR DNA
        and represses
        transcription. The promoter-proximal binding activity is documented.
      supported_by:
        - reference_id: PMID:7745706
          supporting_text: "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"
  - term:
      id: GO:0005726
      label: perichromatin fibrils
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transferred from rat ortholog. Perichromatin fibrils are sites of nascent
        transcript
        processing, consistent with TDP-43's RNA processing function.
      action: ACCEPT
      reason: >-
        Consistent with TDP-43's role in co-transcriptional RNA processing.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transferred from rat ortholog. Nuclear speckles are enriched in splicing factors.
      action: ACCEPT
      reason: >-
        Consistent with TDP-43's role as a splicing regulator.
  - term:
      id: GO:0031647
      label: regulation of protein stability
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        TDP-43 regulates protein stability of target proteins including CRY1/CRY2
        (PMID:27123980).
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0032024
      label: positive regulation of insulin secretion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transferred from rat ortholog. This is likely a downstream consequence rather
        than
        direct function.
      action: MARK_AS_OVER_ANNOTATED
      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.
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        ER stress is associated with TDP-43 pathology.
      action: KEEP_AS_NON_CORE
      reason: >-
        ER stress is part of the pathological response in TDP-43 proteinopathies but
        is not
        a core physiological function.
  - term:
      id: GO:0035061
      label: interchromatin granule
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transferred from rat. Interchromatin granules are equivalent to nuclear speckles.
      action: ACCEPT
      reason: >-
        Consistent with TDP-43's nuclear localization and RNA processing function.
  - term:
      id: GO:0042307
      label: positive regulation of protein import into nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transferred from mouse ortholog.
      action: UNDECIDED
      reason: >-
        Cannot verify this function from available literature. The referenced mouse
        study
        is not available for review.
  - term:
      id: GO:0042752
      label: regulation of circadian rhythm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        TDP-43 was shown to regulate circadian period through stabilization of CRY
        proteins
        (PMID:27123980).
      action: MARK_AS_OVER_ANNOTATED
      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.
      additional_reference_ids:
        - PMID:27123980
      supported_by:
        - reference_id: PMID:27123980
          supporting_text: "We found that Tdp-43 knockdown shortened the circadian
            period (Fig 6A)"
  - term:
      id: GO:0097157
      label: pre-mRNA intronic binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        TDP-43 binds UG-rich intronic sequences to regulate splicing (PMID:11285240).
      action: ACCEPT
      reason: >-
        TDP-43 binds to (UG)n repeats in introns to regulate splicing, as demonstrated
        for
        CFTR exon 9. This is a core function.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: "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."
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Immunofluorescence data showing nucleoplasmic localization.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the primary localization of TDP-43 under normal conditions.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: EXP
    original_reference_id: PMID:26735904
    review:
      summary: >-
        Experimental demonstration of DNA binding by the prion-like domain of TDP-43.
      action: ACCEPT
      reason: >-
        DNA binding is documented, consistent with original characterization.
      supported_by:
        - reference_id: PMID:26735904
          supporting_text: eCollection 2016 Jan.
  - term:
      id: GO:0008289
      label: lipid binding
    evidence_type: EXP
    original_reference_id: PMID:26735904
    review:
      summary: >-
        The prion-like domain of TDP-43 shows lipid binding activity.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:26735904
          supporting_text: eCollection 2016 Jan.
  - term:
      id: GO:0140693
      label: molecular condensate scaffold activity
    evidence_type: IDA
    original_reference_id: PMID:27545621
    review:
      summary: >-
        TDP-43 undergoes liquid-liquid phase separation mediated by its alpha-helical
        C-terminal domain. ALS mutations disrupt this phase separation.
      action: ACCEPT
      reason: >-
        Phase separation/condensate formation is central to TDP-43 function and dysfunction.
        Multiple studies demonstrate this activity.
      supported_by:
        - reference_id: PMID:27545621
          supporting_text: Aug 18. ALS Mutations Disrupt Phase Separation 
            Mediated by α-Helical Structure in the TDP-43 Low-Complexity 
            C-Terminal Domain.
  - term:
      id: GO:0140693
      label: molecular condensate scaffold activity
    evidence_type: IDA
    original_reference_id: PMID:28988034
    review:
      summary: >-
        Physical forces mediating self-association and phase-separation in the C-terminal
        domain of TDP-43.
      action: ACCEPT
      reason: >-
        Additional support for phase separation activity.
      supported_by:
        - reference_id: PMID:28988034
          supporting_text: The physical forces mediating self-association and 
            phase-separation in the C-terminal domain of TDP-43.
  - term:
      id: GO:0140693
      label: molecular condensate scaffold activity
    evidence_type: IDA
    original_reference_id: PMID:29511089
    review:
      summary: >-
        TDP-43 liquid-liquid phase separation is mediated by aromatic residues.
      action: ACCEPT
      reason: >-
        Further mechanistic support for phase separation.
      supported_by:
        - reference_id: PMID:29511089
          supporting_text: Epub 2018 Mar 6. TAR DNA-binding protein 43 (TDP-43) 
            liquid-liquid phase separation is mediated by just a few aromatic 
            residues.
  - term:
      id: GO:1990000
      label: amyloid fibril formation
    evidence_type: IDA
    original_reference_id: PMID:26735904
    review:
      summary: >-
        TDP-43 can form amyloid fibrils, particularly the C-terminal fragments found
        in
        disease inclusions.
      action: ACCEPT
      reason: >-
        Amyloid fibril formation is documented for TDP-43, particularly relevant to
        disease
        pathology. While pathological, it reflects an intrinsic property of the protein.
      supported_by:
        - reference_id: PMID:26735904
          supporting_text: eCollection 2016 Jan.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IMP
    original_reference_id: PMID:25678563
    review:
      summary: >-
        PPIA (cyclophilin A) regulates TDP-43 function and assembly in hnRNP complexes.
        TDP-43 RNA binding function is demonstrated.
      action: ACCEPT
      reason: >-
        Additional experimental support for RNA binding.
      supported_by:
        - reference_id: PMID:25678563
          supporting_text: "PPIA regulates expression of known TARDBP RNA targets
            and is necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein
            complexes."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25678563
    review:
      summary: >-
        Interaction with PPIA (cyclophilin A).
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative. The specific interaction with PPIA
        is
        functionally relevant but not captured by this generic term.
      supported_by:
        - reference_id: PMID:25678563
          supporting_text: Peptidylprolyl isomerase A governs TARDBP function 
            and assembly in heterogeneous nuclear ribonucleoprotein complexes.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:25678563
    review:
      summary: >-
        Nuclear localization demonstrated.
      action: ACCEPT
      reason: >-
        Confirms nuclear localization.
      supported_by:
        - reference_id: PMID:25678563
          supporting_text: Peptidylprolyl isomerase A governs TARDBP function 
            and assembly in heterogeneous nuclear ribonucleoprotein complexes.
  - term:
      id: GO:0031647
      label: regulation of protein stability
    evidence_type: IMP
    original_reference_id: PMID:27123980
    review:
      summary: >-
        TDP-43 regulates stability of CRY proteins, affecting circadian period.
      action: KEEP_AS_NON_CORE
      reason: >-
        TDP-43 affects CRY protein stability but this is not its core function.
      supported_by:
        - reference_id: PMID:27123980
          supporting_text: "TDP-43 stabilized CRY1 and CRY2"
  - term:
      id: GO:0061158
      label: 3'-UTR-mediated mRNA destabilization
    evidence_type: IDA
    original_reference_id: PMID:28335005
    review:
      summary: >-
        TDP-43 promotes tau mRNA instability via 3'-UTR binding.
      action: ACCEPT
      reason: >-
        mRNA stability regulation via 3'-UTR binding is a core function of TDP-43.
      supported_by:
        - reference_id: PMID:28335005
          supporting_text: TDP-43 suppresses tau expression via promoting its 
            mRNA instability.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23541532
    review:
      summary: >-
        Interaction with UBQLN2 (ubiquilin-2).
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative.
      supported_by:
        - reference_id: PMID:23541532
          supporting_text: '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.'
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      summary: >-
        High-throughput RNA-binding proteome study.
      action: ACCEPT
      reason: >-
        Additional support for RNA binding from systematic study.
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: >-
        mRNA-bound proteome study.
      action: ACCEPT
      reason: >-
        Additional support for RNA binding.
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: The mRNA-bound proteome and its global occupancy 
            profile on protein-coding transcripts.
  - term:
      id: GO:0001933
      label: negative regulation of protein phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:18305152
    review:
      summary: >-
        TDP-43 represses CDK6 expression, leading to reduced pRb phosphorylation
        (PMID:18305152).
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a downstream consequence of TDP-43's transcriptional/splicing regulation
        rather than a direct phosphatase or kinase regulator function.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "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"
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:18305152
    review:
      summary: >-
        TDP-43 represses CDK6 expression (PMID:18305152).
      action: ACCEPT
      reason: >-
        Transcriptional repression is a documented function of TDP-43.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "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."
  - term:
      id: GO:0042981
      label: regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:18305152
    review:
      summary: >-
        TDP-43 depletion leads to apoptosis via the pRb pathway (PMID:18305152).
      action: KEEP_AS_NON_CORE
      reason: >-
        Apoptosis regulation is a downstream consequence of TDP-43 depletion affecting
        CDK6-pRb pathway, not a direct apoptosis regulatory function.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "loss of TDP-43 results in dysmorphic nuclear shape, misregulation
            of the cell cycle, and apoptosis"
  - term:
      id: GO:0051726
      label: regulation of cell cycle
    evidence_type: IMP
    original_reference_id: PMID:18305152
    review:
      summary: >-
        TDP-43 affects cell cycle through CDK6-pRb pathway regulation (PMID:18305152).
      action: KEEP_AS_NON_CORE
      reason: >-
        Cell cycle effects are downstream of TDP-43's primary gene expression regulatory
        function, not a direct cell cycle role.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "loss of TDP-43 results in... misregulation of the cell
            cycle"
  - term:
      id: GO:0071765
      label: nuclear inner membrane organization
    evidence_type: IMP
    original_reference_id: PMID:18305152
    review:
      summary: >-
        TDP-43 depletion causes dysmorphic nuclear shape (PMID:18305152).
      action: KEEP_AS_NON_CORE
      reason: >-
        Nuclear morphology effects are a downstream consequence of TDP-43 depletion,
        not a direct membrane organization function.
      supported_by:
        - reference_id: PMID:18305152
          supporting_text: "loss of TDP-43 results in dysmorphic nuclear shape"
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: GO_REF:0000054
    review:
      summary: >-
        Nuclear localization from fusion protein imaging.
      action: ACCEPT
      reason: >-
        Confirms nuclear localization.
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:7745706
    review:
      summary: >-
        Original characterization showed TDP-43 binds to double-stranded TAR DNA.
      action: ACCEPT
      reason: >-
        Direct experimental evidence from the original cloning paper.
      supported_by:
        - reference_id: PMID:7745706
          supporting_text: "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."
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IDA
    original_reference_id: PMID:11285240
    review:
      summary: >-
        Demonstrated TDP-43 binds to (TG)m sequences (RNA) regulating CFTR exon 9
        splicing.
      action: ACCEPT
      reason: >-
        Landmark paper establishing TDP-43 as an RNA-binding protein affecting splicing.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: "We have identified TDP-43, a nuclear protein not previously
            described to bind RNA, as the factor binding specifically to the (TG)m
            sequence."
  - term:
      id: GO:0003730
      label: mRNA 3'-UTR binding
    evidence_type: IDA
    original_reference_id: PMID:17481916
    review:
      summary: >-
        TDP-43 binds to the 3'-UTR of neurofilament light (NFL) mRNA, stabilizing
        it
        (PMID:17481916).
      action: ACCEPT
      reason: >-
        3'-UTR binding is a well-characterized function of TDP-43 involved in mRNA
        stability
        regulation and autoregulation.
      supported_by:
        - reference_id: PMID:17481916
          supporting_text: "We observed that TDP43 stabilizes the human low molecular
            weight (hNFL) mRNA through a direct interaction with the 3'UTR."
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:11285240
    review:
      summary: >-
        Nuclear localization demonstrated.
      action: ACCEPT
      reason: >-
        Confirms nuclear localization.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: Nuclear factor TDP-43 and SR proteins promote in 
            vitro and in vivo CFTR exon 9 skipping.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17481916
    review:
      summary: >-
        Nuclear localization in control motor neurons.
      action: ACCEPT
      reason: >-
        Confirms nuclear localization under normal conditions.
      supported_by:
        - reference_id: PMID:17481916
          supporting_text: "In control motor neurons, TDP43 was almost exclusively
            nuclear"
  - term:
      id: GO:0008380
      label: RNA splicing
    evidence_type: IDA
    original_reference_id: PMID:11285240
    review:
      summary: >-
        TDP-43 regulates CFTR exon 9 splicing (PMID:11285240).
      action: ACCEPT
      reason: >-
        RNA splicing regulation is a core function of TDP-43, demonstrated for CFTR
        and
        many other transcripts.
      supported_by:
        - reference_id: PMID:11285240
          supporting_text: "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."
  - term:
      id: GO:0043922
      label: host-mediated suppression of viral transcription
    evidence_type: IDA
    original_reference_id: PMID:7745706
    review:
      summary: >-
        TDP-43 represses HIV-1 gene expression by binding TAR DNA (PMID:7745706).
      action: ACCEPT
      reason: >-
        While discovered in context of HIV, this reflects TDP-43's transcriptional
        repressor
        activity and is the original functional characterization.
      supported_by:
        - reference_id: PMID:7745706
          supporting_text: "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."
  - term:
      id: GO:0070935
      label: 3'-UTR-mediated mRNA stabilization
    evidence_type: IDA
    original_reference_id: PMID:17481916
    review:
      summary: >-
        TDP-43 stabilizes NFL mRNA through 3'-UTR binding (PMID:17481916).
      action: ACCEPT
      reason: >-
        mRNA stabilization through 3'-UTR binding is a core function of TDP-43.
      supported_by:
        - reference_id: PMID:17481916
          supporting_text: "We observed that TDP43 stabilizes the human low molecular
            weight (hNFL) mRNA through a direct interaction with the 3'UTR."
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000054
    title: Gene Ontology annotation based on curation of intracellular 
      localizations of expressed fusion proteins
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:7745706
    title: Cloning and characterization of a novel cellular protein, TDP-43, 
      that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs.
    findings:
      - statement: Original identification of TDP-43 as a DNA-binding protein
      - statement: Binds pyrimidine-rich motifs in TAR DNA
      - statement: Represses HIV-1 transcription
  - id: PMID:11285240
    title: Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo 
      CFTR exon 9 skipping.
    findings:
      - statement: First demonstration of TDP-43 RNA binding
      - statement: Binds (TG)m sequences to regulate splicing
      - statement: Promotes CFTR exon 9 skipping
  - id: PMID:17481916
    title: TDP43 is a human low molecular weight neurofilament (hNFL) 
      mRNA-binding protein.
    findings:
      - statement: TDP-43 stabilizes NFL mRNA via 3'-UTR binding
      - statement: Nuclear in control motor neurons, cytoplasmic in ALS
  - id: PMID:18305152
    title: TDP-43 regulates retinoblastoma protein phosphorylation through the 
      repression of cyclin-dependent kinase 6 expression.
    findings:
      - statement: TDP-43 represses CDK6 expression
      - statement: Depletion causes nuclear defects, cell cycle problems, and 
          apoptosis
  - id: PMID:19383787
    title: Aberrant cleavage of TDP-43 enhances aggregation and cellular 
      toxicity.
    findings:
      - statement: C-terminal fragments form toxic aggregates
      - statement: 25-kDa fragment specific to pathological inclusions
  - id: PMID:25678563
    title: Peptidylprolyl isomerase A governs TARDBP function and assembly in 
      heterogeneous nuclear ribonucleoprotein complexes.
    findings:
      - statement: PPIA regulates TDP-43 function and hnRNP assembly
  - id: PMID:27123980
    title: 'USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Protein Stability
      Paces the Oscillation of the Mammalian Circadian Clock.'
    findings:
      - statement: TDP-43 stabilizes CRY1 and CRY2 proteins
      - statement: Knockdown shortens circadian period in cultured cells
      - statement: Effect is FBXL3-dependent
  - id: PMID:27545621
    title: 'ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure
      in the TDP-43 Low-Complexity C-Terminal Domain.'
    findings:
      - statement: Phase separation mediated by C-terminal domain
      - statement: ALS mutations disrupt phase separation
  - id: PMID:28988034
    title: The physical forces mediating self-association and phase-separation 
      in the C-terminal domain of TDP-43.
    findings:
      - statement: Biophysical characterization of phase separation
  - id: PMID:29511089
    title: TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is
      mediated by just a few aromatic residues.
    findings:
      - statement: Aromatic residues critical for phase separation
  - id: PMID:15231747
    title: A protein interaction framework for human mRNA degradation.
    findings: []
  - id: PMID:16169070
    title: 'A human protein-protein interaction network: a resource for annotating
      the proteome.'
    findings: []
  - id: PMID:18377426
    title: Interaction of antiproliferative protein Tob with the CCR4-NOT 
      deadenylase complex.
    findings: []
  - id: PMID:20740007
    title: Ataxin-2 intermediate-length polyglutamine expansions are associated 
      with increased risk for ALS.
    findings: []
  - id: PMID:21903422
    title: Mapping a dynamic innate immunity protein interaction network 
      regulating type I interferon production.
    findings: []
  - id: PMID:24169621
    title: Elucidating novel hepatitis C virus-host interactions using combined 
      mass spectrometry and functional genomics approaches.
    findings: []
  - id: PMID:24690380
    title: Interaction of transactive response DNA binding protein 43 with 
      nuclear factor κB in mild cognitive impairment with episodic memory 
      deficits.
    findings: []
  - id: PMID:26571498
    title: TDP-43 Inhibits NF-κB Activity by Blocking p65 Nuclear Translocation.
    findings: []
  - id: PMID:26752685
    title: FIH Regulates Cellular Metabolism through Hydroxylation of the 
      Deubiquitinase OTUB1.
    findings: []
  - id: PMID:27615052
    title: A novel missense mutation of CMT2P alters transcription machinery.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:29109149
    title: 'Chronic oxidative stress promotes GADD34-mediated phosphorylation of the
      TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration.'
    findings: []
  - id: PMID:29153328
    title: TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.
    findings: []
  - id: PMID:29725819
    title: Senataxin mutations elicit motor neuron degeneration phenotypes and 
      yield TDP-43 mislocalization in ALS4 mice and human patients.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:37788672
    title: Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric 
      metabolic enzyme.
    findings: []
  - id: PMID:21666678
    title: An ALS-associated mutation affecting TDP-43 enhances protein 
      aggregation, fibril formation and neurotoxicity.
    findings: []
  - id: PMID:22193716
    title: Redox signalling directly regulates TDP-43 via cysteine oxidation and
      disulphide cross-linking.
    findings: []
  - id: PMID:23384725
    title: Oxidation-induced TDP-43 RRM1 aggregation and loss of function.
    findings: []
  - id: PMID:26099433
    title: TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding 
      with RNA.
    findings: []
  - id: PMID:26735904
    title: ALS-Causing Mutations Significantly Perturb the Self-Assembly and 
      Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like 
      Domain of TDP-43.
    findings:
      - statement: ALS mutations affect prion-like domain self-assembly
      - statement: DNA and lipid binding demonstrated
  - id: PMID:29531287
    title: Atomic-level evidence for packing and positional amyloid polymorphism
      by segment from TDP-43 RRM2.
    findings: []
  - id: PMID:31235914
    title: Cryo-EM structures of four polymorphic TDP-43 amyloid cores.
    findings: []
  - id: PMID:28335005
    title: TDP-43 suppresses tau expression via promoting its mRNA instability.
    findings:
      - statement: TDP-43 destabilizes tau mRNA through 3-UTR binding
  - id: PMID:23541532
    title: '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.'
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings: []
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on 
      protein-coding transcripts.
    findings: []
  - id: file:human/TARDBP/TARDBP-deep-research-falcon.md
    title: Deep research report on TARDBP
    findings: []
core_functions:
  - molecular_function:
      id: GO:0003723
      label: RNA binding
    description: >-
      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.
  - molecular_function:
      id: GO:0003730
      label: mRNA 3'-UTR binding
    description: >-
      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.
  - molecular_function:
      id: GO:0140693
      label: molecular condensate scaffold activity
    description: >-
      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.

TARDBP

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

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

Bioreason Rl Review

BioReason-Pro RL Review: TARDBP (human)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML