Tardbp encodes TDP-43 (TAR DNA-binding protein 43), a ubiquitously expressed, predominantly nuclear hnRNP-like RNA-binding protein with an N-terminal self-association domain carrying a nuclear localization signal, two RNA recognition motifs that bind UG/TG-rich RNA and single-stranded DNA, and a glycine-rich C-terminal low-complexity domain that drives phase separation. In rat cortical neurons it binds thousands of transcripts at (UG)n motifs in introns, exons and 3'-UTRs and localizes to perichromatin fibrils, the sites of transcription and co-transcriptional splicing. TDP-43 regulates alternative pre-mRNA splicing, notably repressing non-conserved cryptic exons, and controls mRNA stability through 3'-UTR binding, including negative autoregulation of its own transcript. It shuttles to the cytoplasm, where it joins RNP granules, and its nuclear loss with cytoplasmic aggregation is the hallmark pathology of ALS and frontotemporal lobar degeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Chromatin IBA from the TDP-43 PANTHER node (seeded by fly and rat rows). Reason: TDP-43 is concentrated in perichromatin fibrils at sites of transcription and binds TG-rich DNA, so association with chromatin is plausible and inherited across the clade, but chromatin is not where its core RNA-processing activity is defined. Kept as non-core. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. 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:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Sequence-specific binding to RNA polymerase II cis-regulatory DNA, transferred from mouse (MGI IDA, PMID:18836447). Reason: The mouse source paper identified proteins binding the Shh SBE2 enhancer by DNA pull-down and mass spectrometry; the cached full text does not name TDP-43 (probably listed in a supplementary table), so the source row could not be checked directly. Independently, human TDP-43 was discovered as a factor binding double-stranded promoter TAR DNA of the HIV-1 LTR and repressing transcription, so promoter DNA binding is a real but minor, non-core activity next to RNA processing. 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. PMID:18836447 DNA/protein complexes were pulled-down with streptavidin-coated agarose beads and their protein content analyzed by mass spectrometry |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Sequence-specific binding to RNA polymerase II cis-regulatory DNA, transferred from mouse (MGI IDA, PMID:18836447). Reason: The mouse source paper identified proteins binding the Shh SBE2 enhancer by DNA pull-down and mass spectrometry; the cached full text does not name TDP-43 (probably listed in a supplementary table), so the source row could not be checked directly. Independently, human TDP-43 was discovered as a factor binding double-stranded promoter TAR DNA of the HIV-1 LTR and repressing transcription, so promoter DNA binding is a real but minor, non-core activity next to RNA processing. 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. PMID:18836447 DNA/protein complexes were pulled-down with streptavidin-coated agarose beads and their protein content analyzed by mass spectrometry |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MODIFY | Summary: Nucleic acid binding from InterPro RBD domain superfamily mapping. Reason: True but uninformative. TDP-43 binds UG-rich RNA through its two RRMs, specifically intronic pre-mRNA sites and mRNA 3'-UTRs, as shown for rat neurons by RIP-seq; replace with these specific terms, which the gene already carries. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21051541 To identify RNAs associating with TDP-43, we used a modified RNA immunoprecipitation method followed by deep sequencing (RIP-seq) (27) from primary cultured rat cortical neurons PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. PMID:21358640 we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo |
| GO:0003677 DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: DNA binding by ISO from human TDP-43 (EXP, PMID:26735904). Reason: The human source shows single-stranded DNA binding to the prion-like domain, and the founding paper showed binding of double-stranded TAR DNA. Both specific terms are supported; DNA binding is too general. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q13148 SUPPORTS TRANSFER Human EXP row is sound; it supports single-stranded DNA binding, a more specific term. Proposed replacements: single-stranded DNA binding double-stranded DNA binding Supporting Evidence: PMID:26735904 ssDNA was able to bind and trigger the significant conformational changes for the wild-type prion-like domain 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:0003690 double-stranded DNA binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Double-stranded DNA binding transferred from human TDP-43. Reason: Human TDP-43 was named for binding double-stranded TAR DNA via its RRMs. The RRMs are conserved in rat, so the transfer is sound, but DNA binding is peripheral to the RNA-processing core function. 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:0003690 double-stranded DNA binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Double-stranded DNA binding transferred from human TDP-43. Reason: Human TDP-43 was named for binding double-stranded TAR DNA via its RRMs. The RRMs are conserved in rat, so the transfer is sound, but DNA binding is peripheral to the RNA-processing core function. 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 | IBA GO_REF:0000033 | MODIFY | Summary: RNA binding IBA from the TDP-43 PANTHER node (PTN002689978); rat Tardbp itself is among the seeds. Reason: RNA binding is inherited across the clade and the target appears in its own WITH/FROM because of its own RIP-seq IDA. The term is true but general: TDP-43 RRMs bind UG-rich intronic pre-mRNA and mRNA 3'-UTR sites, shown in rat neurons. Replace with those specific terms, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002689978 SUPPORTS TRANSFER Node placement is sound for the TDP-43 orthologue group; only granularity is at issue. RGD:1310906 SUPPORTS TRANSFER Rat Tardbp own IDA (PMID:21051541) is part of the descendant evidence, as expected. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21051541 To identify RNAs associating with TDP-43, we used a modified RNA immunoprecipitation method followed by deep sequencing (RIP-seq) (27) from primary cultured rat cortical neurons PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. PMID:21358640 we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo |
| GO:0003723 RNA binding | IDA PMID:21051541 Identification of neuronal RNA targets of TDP-43-containing ... | MODIFY | Summary: RIP-seq of endogenous TDP-43 from primary rat cortical neurons identifies thousands of bound RNAs, enriched for (UG)n motifs, with intronic, exonic and 3'-UTR binding. Reason: This is the key rat experiment and the binding is real, but the data support more specific terms: intronic pre-mRNA binding (most reads intronic) and 3'-UTR binding (pronounced exonic reads in 3'-UTRs). Replace RNA binding with both. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21051541 To identify RNAs associating with TDP-43, we used a modified RNA immunoprecipitation method followed by deep sequencing (RIP-seq) (27) from primary cultured rat cortical neurons PMID:21051541 The number of these sequences in TDP-43 showed a remarkable 55.1-fold enrichment when compared with the control library PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. PMID:21051541 We noticed a pronounced representation of exonic reads in the 3β²-UTR and intronic reads in the 5β²-UTR in a subset of TDP-43 targets |
| GO:0003723 RNA binding | IEA GO_REF:0000120 | MODIFY | Summary: RNA binding from combined automated methods (ARBA, InterPro RRM, orthologues). Reason: True but general; the specific RNA-binding modes (intronic pre-mRNA and mRNA 3'-UTR) are established for TDP-43 including in rat neurons. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21051541 To identify RNAs associating with TDP-43, we used a modified RNA immunoprecipitation method followed by deep sequencing (RIP-seq) (27) from primary cultured rat cortical neurons PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. |
| GO:0003723 RNA binding | ISO GO_REF:0000121 | MODIFY | Summary: RNA binding by ISO from mouse TDP-43 (MGI IDA, CLIP-based). Reason: Mouse brain CLIP-seq shows TDP-43 binding of intronic sites and of its own 3'-UTR; the sound transfer is better expressed by the specific terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2387629 SUPPORTS TRANSFER Mouse experimental RNA binding is sound and orthologous; only granularity is at issue. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. |
| GO:0003723 RNA binding | ISO GO_REF:0000121 | MODIFY | Summary: RNA binding by ISO from human TDP-43. Reason: Human TDP-43 binds UG-rich RNA clusters (iCLIP) and its own 3'-UTR; replace with the specific terms supported in rat as well. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q13148 SUPPORTS TRANSFER Human experimental RNA binding is sound; only granularity is at issue. Proposed replacements: pre-mRNA intronic binding mRNA 3'-UTR binding Supporting Evidence: PMID:21358640 we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. |
| GO:0003730 mRNA 3'-UTR binding | IEA GO_REF:0000107 | ACCEPT | Summary: mRNA 3'-UTR binding transferred from human TDP-43. Reason: TDP-43 binds 3'-UTR sequences of its own mRNA (autoregulation) and of targets such as NFL and tau mRNA; rat RIP-seq shows prominent 3'-UTR reads. Core activity. Supporting Evidence: PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. PMID:17481916 We observed that TDP43 stabilizes the human low molecular weight (hNFL) mRNA through a direct interaction with the 3'UTR. PMID:21051541 We noticed a pronounced representation of exonic reads in the 3β²-UTR and intronic reads in the 5β²-UTR in a subset of TDP-43 targets |
| GO:0003730 mRNA 3'-UTR binding | ISO GO_REF:0000121 | ACCEPT | Summary: mRNA 3'-UTR binding transferred from human TDP-43. Reason: TDP-43 binds 3'-UTR sequences of its own mRNA (autoregulation) and of targets such as NFL and tau mRNA; rat RIP-seq shows prominent 3'-UTR reads. Core activity. Supporting Evidence: PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. PMID:17481916 We observed that TDP43 stabilizes the human low molecular weight (hNFL) mRNA through a direct interaction with the 3'UTR. PMID:21051541 We noticed a pronounced representation of exonic reads in the 3β²-UTR and intronic reads in the 5β²-UTR in a subset of TDP-43 targets |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization of TDP-43 (automated and orthologue transfer). Reason: TDP-43 is a predominantly nuclear hnRNP-like protein; in rat neurons it is concentrated in nuclear perichromatin fibrils. Nucleus is where its splicing and autoregulatory activities occur. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: Nuclear localization of TDP-43 (automated and orthologue transfer). Reason: TDP-43 is a predominantly nuclear hnRNP-like protein; in rat neurons it is concentrated in nuclear perichromatin fibrils. Nucleus is where its splicing and autoregulatory activities occur. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: Nuclear localization of TDP-43 (automated and orthologue transfer). Reason: TDP-43 is a predominantly nuclear hnRNP-like protein; in rat neurons it is concentrated in nuclear perichromatin fibrils. Nucleus is where its splicing and autoregulatory activities occur. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005654 nucleoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Nucleoplasm localization (IBA from TDP-43 node; Ensembl and RGD ISO from human). Reason: Consistent with rat immunoelectron microscopy placing TDP-43 in euchromatin perichromatin fibrils, which lie in the nucleoplasm, and with conservation across the clade. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Nucleoplasm localization (IBA from TDP-43 node; Ensembl and RGD ISO from human). Reason: Consistent with rat immunoelectron microscopy placing TDP-43 in euchromatin perichromatin fibrils, which lie in the nucleoplasm, and with conservation across the clade. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005654 nucleoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Nucleoplasm localization (IBA from TDP-43 node; Ensembl and RGD ISO from human). Reason: Consistent with rat immunoelectron microscopy placing TDP-43 in euchromatin perichromatin fibrils, which lie in the nucleoplasm, and with conservation across the clade. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005726 perichromatin fibrils | IDA PMID:19539030 TDP-43 localizes in mRNA transcription and processing sites ... | ACCEPT | Summary: Immunoelectron microscopy in rat neurons localizes TDP-43 to perichromatin fibrils, sites of transcription and co-transcriptional splicing. Reason: Direct rat evidence (abstract read; curator saw full text) and the specific nuclear site where co-transcriptional splicing regulation occurs. Supporting Evidence: PMID:19539030 TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cytoplasm localization (ARBA prediction; ISO from mouse EXP PMID:30464263 and human). Reason: TDP-43 shuttles to the cytoplasm, where it forms RNP assemblies such as myo-granules in regenerating muscle and stress granules; this is real but secondary to its nuclear role. Supporting Evidence: PMID:30464263 TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cytoplasm localization (ARBA prediction; ISO from mouse EXP PMID:30464263 and human). Reason: TDP-43 shuttles to the cytoplasm, where it forms RNP assemblies such as myo-granules in regenerating muscle and stress granules; this is real but secondary to its nuclear role. Supporting Evidence: PMID:30464263 TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cytoplasm localization (ARBA prediction; ISO from mouse EXP PMID:30464263 and human). Reason: TDP-43 shuttles to the cytoplasm, where it forms RNP assemblies such as myo-granules in regenerating muscle and stress granules; this is real but secondary to its nuclear role. Supporting Evidence: PMID:30464263 TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrion (UniProt subcellular-location mapping; ISO from human). Reason: The human claim rests mainly on TDP-43 accumulation in neuronal mitochondria in ALS/FTD tissue and with disease mutants; the organelle claim is kept per the organelle policy (no sub-compartment is asserted) but it is not a site of the core function and its physiological extent is debated. Supporting Evidence: PMID:27348499 Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mitochondrion (UniProt subcellular-location mapping; ISO from human). Reason: The human claim rests mainly on TDP-43 accumulation in neuronal mitochondria in ALS/FTD tissue and with disease mutants; the organelle claim is kept per the organelle policy (no sub-compartment is asserted) but it is not a site of the core function and its physiological extent is debated. Supporting Evidence: PMID:27348499 Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). |
| GO:0008289 lipid binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Lipid binding by ISO from human TDP-43 (EXP, PMID:26735904). Reason: The human study maps a membrane-interacting subdomain (Met311-Gln343) in the C-terminal region using membrane mimetics. The residues are conserved in rat; the activity is real in vitro but peripheral. Supporting Evidence: PMID:26735904 A membrane-interacting subdomain has been identified over residues Met311-Gln343 indispensable for TDP-43 neurotoxicity |
| GO:0008380 RNA splicing | IEA GO_REF:0000120 | MODIFY | Summary: RNA splicing (ARBA/orthologue combined IEA). Reason: TDP-43 is not a core spliceosome component; it is a splicing regulator that represses or enhances specific exons (cryptic exons, CFTR exon 9) in a position-dependent manner. Replace with regulation of alternative mRNA splicing. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome Supporting Evidence: PMID:21358640 binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins PMID:26250685 we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity 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:0008380 RNA splicing | ISO GO_REF:0000121 | MODIFY | Summary: RNA splicing (acts upstream of or within) by ISO from mouse IMP (PMID:27378374): TDP-43 depletion in mouse striatum alters splicing. Reason: Depletion of TDP-43 from mouse brain alters hundreds of splicing events; together with direct intronic binding this establishes TDP-43 as a regulator of alternative splicing rather than a participant in splicing chemistry. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:2387629 SUPPORTS TRANSFER Mouse knockdown splicing changes are sound; term should be the regulatory one. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome Supporting Evidence: PMID:21358643 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides PMID:27378374 we re-analysed RNA-seq data sets in which FUS and TDP-43 were depleted from the mouse striatum in the same manner as TAF15 |
| GO:0008380 RNA splicing | ISO GO_REF:0000121 | MODIFY | Summary: RNA splicing by ISO from human TDP-43 (IDA PMID:11285240, CFTR exon 9). Reason: The human source shows TDP-43 promoting skipping of CFTR exon 9 by binding (UG)m near the 3' splice site, i.e. regulation of alternative splicing. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q13148 SUPPORTS TRANSFER Human source is sound; it supports the regulatory splicing term. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome 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. PMID:26250685 we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity |
| GO:0010467 gene expression | ISO GO_REF:0000121 | MODIFY | Summary: Gene expression (acts upstream of or within) by ISO from mouse IMP (PMID:27378374). Reason: TDP-43 depletion changes mRNA levels and splicing in mouse brain. The specific, mechanistically grounded roles are regulation of alternative splicing and 3'-UTR-mediated mRNA destabilization. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2387629 SUPPORTS TRANSFER Mouse knockdown data are sound; the term is too general. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome 3'-UTR-mediated mRNA destabilization Supporting Evidence: PMID:21358643 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation |
| GO:0010468 regulation of gene expression | IBA GO_REF:0000033 | MODIFY | Summary: Regulation of gene expression IBA from the TDP-43 node. Reason: True for the clade but general. TDP-43 regulates gene expression specifically by controlling alternative splicing (including cryptic exon repression) and by 3'-UTR-mediated mRNA destabilization (autoregulation, tau); both are descendants of regulation of gene expression and are carried by this gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002689978 SUPPORTS TRANSFER Node placement is sound; only granularity is at issue. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome 3'-UTR-mediated mRNA destabilization Supporting Evidence: PMID:26250685 we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity PMID:21358640 binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | MODIFY | Summary: Negative regulation of gene expression from human TDP-43 (IMP PMID:18305152, Cdk6 repression). Reason: TDP-43 represses targets including Cdk6, tau and its own mRNA; the best-characterised mechanism is 3'-UTR-mediated mRNA destabilization, a descendant term the gene carries. Proposed replacements: 3'-UTR-mediated mRNA destabilization Supporting Evidence: PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. PMID:28335005 Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | MODIFY | Summary: Negative regulation of gene expression from human TDP-43 (IMP PMID:18305152, Cdk6 repression). Reason: TDP-43 represses targets including Cdk6, tau and its own mRNA; the best-characterised mechanism is 3'-UTR-mediated mRNA destabilization, a descendant term the gene carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q13148 SUPPORTS TRANSFER Human source sound; term is general. Proposed replacements: 3'-UTR-mediated mRNA destabilization Supporting Evidence: PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. PMID:28335005 Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. |
| GO:0016607 nuclear speck | IDA PMID:19539030 TDP-43 localizes in mRNA transcription and processing sites ... | KEEP AS NON CORE | Summary: Immunolabeling in rat neurons shows weak TDP-43 signal in nuclear speckles of splicing factors. Reason: Direct rat evidence (abstract only; defer to curator), but the abstract describes only weak speckle labelling; perichromatin fibrils are the main site. Supporting Evidence: PMID:19539030 a weak TDP-43 immunolabeling is found in nuclear speckles of splicing factors |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Regulation of protein stability (ISO from mouse IMP PMID:27123980 and human; ARBA). Reason: TDP-43 stabilizes CRY1 and CRY2 proteins in cultured cells; this is a documented but peripheral role. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of protein stability (ISO from mouse IMP PMID:27123980 and human; ARBA). Reason: TDP-43 stabilizes CRY1 and CRY2 proteins in cultured cells; this is a documented but peripheral role. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of protein stability (ISO from mouse IMP PMID:27123980 and human; ARBA). Reason: TDP-43 stabilizes CRY1 and CRY2 proteins in cultured cells; this is a documented but peripheral role. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. |
| GO:0032024 positive regulation of insulin secretion | IMP PMID:21127054 Class II phosphoinositide 3-kinase regulates exocytosis of i... | REMOVE | Summary: RGD IMP for positive regulation of insulin secretion citing a study of PI3K-C2alpha in rat insulinoma cells. Reason: The full text of PMID:21127054 was read: it studies knockdown of PI3K-C2alpha (Pik3c2a) and never mentions TDP-43 or Tardbp. The annotation is very likely attached to the wrong rat gene. Supporting Evidence: PMID:21127054 down-regulation of the class II PI3K isoform PI3K-C2Ξ± specifically impairs insulin granule exocytosis in rat insulinoma cells |
| GO:0034976 response to endoplasmic reticulum stress | IEP PMID:21608013 Amino acid analog toxicity in primary rat neuronal and astro... | MODIFY | Summary: IEP: amino-acid analogues that cause protein misfolding raise TDP-43 levels in rat neurons and astrocytes. Reason: Full text read. The study induces general protein misfolding with canavanine and AZC and measures increased TDP-43 levels; it does not examine the endoplasmic reticulum or ER stress markers. The expression response is better captured by response to misfolded protein. Proposed replacements: response to misfolded protein Supporting Evidence: PMID:21608013 Amino acid analogs induced increased levels of TDP-43 and its cleavage products. PMID:21608013 This study suggest that TDP-43 expression, and the generation of the ~35 kDa TDP-43 fragment is rapidly induced in neurons following increases in protein misfolding. |
| GO:0035061 interchromatin granule | IDA PMID:19539030 TDP-43 localizes in mRNA transcription and processing sites ... | KEEP AS NON CORE | Summary: Immunoelectron microscopy in rat neurons places TDP-43 in nuclear compartments including interchromatin granule clusters (speckles). Reason: Direct rat evidence (abstract only; defer to curator). The abstract reports only weak labelling of splicing-factor speckles (interchromatin granule clusters), so this is a minor location. Supporting Evidence: PMID:19539030 a weak TDP-43 immunolabeling is found in nuclear speckles of splicing factors |
| GO:0042307 positive regulation of protein import into nucleus | IEA GO_REF:0000107 | REMOVE | Summary: Positive regulation of protein import into nucleus, Ensembl Compara transfer from mouse (UniProt IDA PMID:28585542). Reason: The mouse source paper shows CHCHD10 maintaining nuclear TDP-43; TDP-43 is the imported cargo, not a regulator of import. The electronic transfer propagates a role conflation. Supporting Evidence: PMID:28585542 CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43 |
| GO:0042307 positive regulation of protein import into nucleus | ISO GO_REF:0000121 | REMOVE | Summary: Positive regulation of protein import into nucleus by ISO from mouse (UniProt IDA PMID:28585542). Reason: Same source as the IEA row: in PMID:28585542 TDP-43 is the cargo whose nuclear retention depends on CHCHD10. There is no evidence that TDP-43 regulates nuclear import of other proteins. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:2387629 SOURCE BAD Mouse row assigns the regulator role to the cargo (TDP-43) instead of CHCHD10. Supporting Evidence: PMID:28585542 CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43 |
| GO:0042752 regulation of circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of circadian rhythm from mouse (UniProt IMP PMID:27123980). Reason: TDP-43 knockdown shortened the circadian period in cultured cells, attributed to loss of CRY1/CRY2 stabilization. Real but peripheral. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. |
| GO:0042752 regulation of circadian rhythm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of circadian rhythm from mouse (UniProt IMP PMID:27123980). Reason: TDP-43 knockdown shortened the circadian period in cultured cells, attributed to loss of CRY1/CRY2 stabilization. Real but peripheral. Supporting Evidence: PMID:27123980 TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Identical protein binding from human TDP-43 (multiple IPI). Reason: TDP-43 self-associates through its N-terminal domain and C-terminal helical segment; self-assembly underlies condensate formation. Retained as non-core; the informative activity is captured by molecular condensate scaffold activity. Supporting Evidence: PMID:27545621 we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation PMID:26735904 ssDNA was able to bind and trigger the significant conformational changes for the wild-type prion-like domain |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Identical protein binding from human TDP-43 (multiple IPI). Reason: TDP-43 self-associates through its N-terminal domain and C-terminal helical segment; self-assembly underlies condensate formation. Retained as non-core; the informative activity is captured by molecular condensate scaffold activity. Supporting Evidence: PMID:27545621 we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation PMID:26735904 ssDNA was able to bind and trigger the significant conformational changes for the wild-type prion-like domain |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Regulation of apoptotic process from human knockdown (IMP PMID:18305152). Reason: Apoptosis after TDP-43 depletion is a downstream consequence of Cdk6/pRb deregulation; TDP-43 performs no step of the apoptotic process. Knockdown phenotype only. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. |
| GO:0042981 regulation of apoptotic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Regulation of apoptotic process from human knockdown (IMP PMID:18305152). Reason: Apoptosis after TDP-43 depletion is a downstream consequence of Cdk6/pRb deregulation; TDP-43 performs no step of the apoptotic process. Knockdown phenotype only. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q13148 SOURCE WEAK OR INFERRED Human source is a knockdown phenotype downstream of Cdk6 derepression. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. |
| GO:0043922 host-mediated suppression of viral transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Host-mediated suppression of viral transcription from human TDP-43 (IDA PMID:7745706). Reason: The human finding is repression of HIV-1 LTR transcription in vitro and in transfected cells, the observation that named the protein. There is no evidence of a physiological antiviral role, and rat is not an HIV-1 host; transfer to rat over-states it. 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 |
| GO:0043922 host-mediated suppression of viral transcription | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Host-mediated suppression of viral transcription from human TDP-43 (IDA PMID:7745706). Reason: The human finding is repression of HIV-1 LTR transcription in vitro and in transfected cells, the observation that named the protein. There is no evidence of a physiological antiviral role, and rat is not an HIV-1 host; transfer to rat over-states it. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q13148 SUPPORTS SOURCE BUT NOT TARGET In vitro HIV-1 LTR repression by human TDP-43; no physiological viral context in rat. 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 |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Regulation of cell cycle from human knockdown (IMP PMID:18305152). Reason: Cell-cycle misregulation after TDP-43 depletion results from derepression of one target (Cdk6); TDP-43 is a general RNA-processing factor, not a cell-cycle regulator. Knockdown phenotype only. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. |
| GO:0051726 regulation of cell cycle | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Regulation of cell cycle from human knockdown (IMP PMID:18305152). Reason: Cell-cycle misregulation after TDP-43 depletion results from derepression of one target (Cdk6); TDP-43 is a general RNA-processing factor, not a cell-cycle regulator. Knockdown phenotype only. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q13148 SOURCE WEAK OR INFERRED Knockdown phenotype downstream of Cdk6 derepression. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis PMID:18305152 Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. |
| GO:0061158 3'-UTR-mediated mRNA destabilization | IEA GO_REF:0000107 | ACCEPT | Summary: 3'-UTR-mediated mRNA destabilization from human TDP-43 (IDA PMID:28335005). Reason: TDP-43 destabilizes tau mRNA and, through binding its own 3'-UTR, its own transcript (autoregulation via 3'-UTR intron splicing and decay), a conserved function shown in mouse brain. Supporting Evidence: PMID:28335005 Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. |
| GO:0061158 3'-UTR-mediated mRNA destabilization | ISO GO_REF:0000121 | ACCEPT | Summary: 3'-UTR-mediated mRNA destabilization from human TDP-43 (IDA PMID:28335005). Reason: TDP-43 destabilizes tau mRNA and, through binding its own 3'-UTR, its own transcript (autoregulation via 3'-UTR intron splicing and decay), a conserved function shown in mouse brain. Supporting Evidence: PMID:28335005 Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation PMID:21131904 The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. |
| GO:0070935 3'-UTR-mediated mRNA stabilization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: 3'-UTR-mediated mRNA stabilization from human TDP-43 (IDA PMID:17481916, NFL mRNA). Reason: TDP-43 stabilizes human NFL mRNA by direct 3'-UTR interaction; a documented target-specific effect, peripheral to the core splicing and autoregulatory roles. 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:0070935 3'-UTR-mediated mRNA stabilization | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: 3'-UTR-mediated mRNA stabilization from human TDP-43 (IDA PMID:17481916, NFL mRNA). Reason: TDP-43 stabilizes human NFL mRNA by direct 3'-UTR interaction; a documented target-specific effect, peripheral to the core splicing and autoregulatory roles. 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:0071765 nuclear inner membrane organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Nuclear inner membrane organization from human knockdown (IMP PMID:18305152). Reason: Dysmorphic nuclear shape after TDP-43 depletion is mediated via the pRb pathway; TDP-43 does not participate in organizing the nuclear inner membrane. Knockdown phenotype only. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis |
| GO:0071765 nuclear inner membrane organization | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Nuclear inner membrane organization from human knockdown (IMP PMID:18305152). Reason: Dysmorphic nuclear shape after TDP-43 depletion is mediated via the pRb pathway; TDP-43 does not participate in organizing the nuclear inner membrane. Knockdown phenotype only. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q13148 SOURCE WEAK OR INFERRED Indirect knockdown phenotype. Supporting Evidence: PMID:18305152 loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis |
| GO:0097157 pre-mRNA intronic binding | IEA GO_REF:0000107 | ACCEPT | Summary: Pre-mRNA intronic binding from mouse (MGI IDA PMID:27378374, CLIP-seq). Reason: TDP-43 binds long UG-rich clusters deep in introns (human and mouse CLIP) and most rat RIP-seq reads map to introns. Core activity underlying splicing regulation. Supporting Evidence: PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. PMID:21358640 we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation |
| GO:0097157 pre-mRNA intronic binding | ISO GO_REF:0000121 | ACCEPT | Summary: Pre-mRNA intronic binding from mouse (MGI IDA PMID:27378374, CLIP-seq). Reason: TDP-43 binds long UG-rich clusters deep in introns (human and mouse CLIP) and most rat RIP-seq reads map to introns. Core activity underlying splicing regulation. Supporting Evidence: PMID:21051541 These results, taken together, suggest that TDP-43 regulates genes in three different modes. One is through binding sites in introns, one is through binding sites in exons, and another is through binding across both introns and exons. PMID:21358640 we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo PMID:21358643 TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation |
| GO:0140693 molecular condensate scaffold activity | IEA GO_REF:0000107 | ACCEPT | Summary: Molecular condensate scaffold activity from human TDP-43 (IDA, LLPS studies). Reason: The TDP-43 C-terminal low-complexity domain (conserved in rat, Pfam TDP-43_C) drives liquid-liquid phase separation via a transient alpha-helix and aromatic residues; this scaffolds nuclear bodies and RNP granules. Supporting Evidence: PMID:27545621 we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation PMID:29511089 three tryptophan residues and, to a lesser extent, four other aromatic residues are most important for TDP-43 to undergo LLPS |
| GO:0140693 molecular condensate scaffold activity | ISO GO_REF:0000121 | ACCEPT | Summary: Molecular condensate scaffold activity from human TDP-43 (IDA, LLPS studies). Reason: The TDP-43 C-terminal low-complexity domain (conserved in rat, Pfam TDP-43_C) drives liquid-liquid phase separation via a transient alpha-helix and aromatic residues; this scaffolds nuclear bodies and RNP granules. Supporting Evidence: PMID:27545621 we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation PMID:29511089 three tryptophan residues and, to a lesser extent, four other aromatic residues are most important for TDP-43 to undergo LLPS |
| GO:1990000 amyloid fibril formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Amyloid fibril formation from human TDP-43 (IDA PMID:26735904). Reason: TDP-43 forms amyloid-like assemblies physiologically (myo-granules in regenerating muscle) and pathologically; real, but secondary to its RNA-processing function. Supporting Evidence: PMID:30464263 TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules |
| GO:1990000 amyloid fibril formation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Amyloid fibril formation from human TDP-43 (IDA PMID:26735904). Reason: TDP-43 forms amyloid-like assemblies physiologically (myo-granules in regenerating muscle) and pathologically; real, but secondary to its RNA-processing function. Supporting Evidence: PMID:30464263 TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules |
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Download this section (compressed HTML)Q: Does RGD:1310906 carry the positive regulation of insulin secretion IMP (PMID:21127054) in error for Pik3c2a?
Q: Which rat neuronal transcripts contain TDP-43-repressed cryptic exons, and do they overlap the human STMN2/UNC13A set given poor intronic conservation?
Q: Is endogenous rat TDP-43 present inside mitochondria under physiological conditions, or only after overexpression or in disease models?
Experiment: iCLIP or eCLIP of endogenous TDP-43 in rat cortical neurons combined with TDP-43 knockdown RNA-seq to map binding sites to cryptic exon repression and 3'-UTR-mediated decay targets at nucleotide resolution.
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