Phosphorylation of the compartmentalized PKA substrate TAF15 regulates RNA:Protein interactions
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB72107 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Spatiotemporal-controlled second messengers alter molecular interactions of central signaling nodes for ensuring physiological signal transmission. One prototypical second messenger molecule which modulates kinase signal transmission is the cyclic-adenosine monophosphate (cAMP). The main proteinogenic cellular effectors of cAMP are compartmentalized protein kinase A (PKA) complexes. Their cell-type specific compositions precisely coordinate substrate phosphorylation and proper signal propagation which is indispensable for numerous cell-type specific functions. Here we present evidence that TAF15, which is implicated in the etiology of amyotrophic lateral sclerosis, represents a novel nuclear PKA substrate. In cross-linking and immunoprecipitation experiments (iCLIP) we showed that TAF15 phosphorylation alters the binding to target transcripts related to mRNA maturation, splicing and protein-binding related functions. TAF15 appears to be one of multiple PKA substrates that undergo RNA-binding dynamics upon phosphorylation. We observed that the activation of the cAMP-PKA signaling axis caused a change in the composition of a collection of RNA species that interact with TAF15. This observation appears to be a broader principle in the regulation of molecular interactions, as we identified a significant enrichment of RNA-binding proteins within endogenous PKA complexes. We assume that phosphorylation of RNA-binding domains adds another layer of regulation to binary protein-RNAs interactions with consequences to RNA features including binding specificities, localization, abundance and composition.
2024-04-04 | PXD048869 | Pride
Project description:Spatiotemporal-controlled second messengers alter molecular interactions of central signaling nodes for ensuring physiological signal transmission. One prototypical second messenger molecule which modulates kinase signal transmission is the cyclic-adenosine monophosphate (cAMP). The main proteinogenic cellular effectors of cAMP are compartmentalized protein kinase A (PKA) complexes. Their cell-type specific compositions precisely coordinate substrate phosphorylation and proper signal propagation which is indispensable for numerous cell-type specific functions. Here we present evidence that TAF15, which is implicated in the etiology of amyotrophic lateral sclerosis, represents a novel nuclear PKA substrate. In cross-linking and immunoprecipitation experiments (iCLIP) we showed that TAF15 phosphorylation alters the binding to target transcripts related to mRNA maturation, splicing and protein-binding related functions. TAF15 appears to be one of multiple PKA substrates that undergo RNA-binding dynamics upon phosphorylation. We observed that the activation of the cAMP-PKA signaling axis caused a change in the composition of a collection of RNA species that interact with TAF15. This observation appears to be a broader principle in the regulation of molecular interactions, as we identified a significant enrichment of RNA-binding proteins within endogenous PKA complexes. We assume that phosphorylation of RNA-binding domains adds another layer of regulation to binary protein-RNAs interactions with consequences to RNA features including binding specificities, localization, abundance and composition.
| S-EPMC10991009 | biostudies-literature
Project description:TAF15 (formerly TAFII68) is a member of the TET family of RNA and DNA binding proteins whose genes are frequently translocated in sarcomas. Consistent with a functional role in cell viability, TAF15 depletion had a growth-inhibitory effect and increased apoptosis. Interestingly, one of the genes affected by TAF15 depletion is CDKN1A/p21, a key regulator of cell cycle. Here we show that TAF15 down-regulates CDKN1A/p21 expression through a pathway involving miRNAs.
2012-12-21 | GSE34470 | GEO
Project description:TAF15 (formerly TAFII68) is a member of the TET family of RNA and DNA binding proteins whose genes are frequently translocated in sarcomas. Consistent with a functional role in cell viability, TAF15 depletion had a growth-inhibitory effect and increased apoptosis. Interestingly, one of the genes affected by TAF15 depletion is CDKN1A/p21, a key regulator of cell cycle. Here we show that TAF15 down-regulates CDKN1A/p21 expression through a pathway involving miRNAs. We performed a gene expression profiling upon TAF15 knock down by RNA interference.Total RNAs purified from four biological replicates of HeLa GL3 luc cells transfected either with si-TAF15 or control si-LUC were hybridized to the array.
2012-12-21 | E-GEOD-34470 | biostudies-arrayexpress
Project description:Frontotemporal dementia (FTD) is the most common form of dementia after Alzheimer's disease and results from frontotemporal lobar degeneration (FTLD). The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins1. In the majority of cases, the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterising different FTLD subtypes2,3. The presence, identities and structures of amyloid filaments in the remaining ~10% of FTLD cases are unknown, but are widely believed to be composed of the protein fused in sarcoma (FUS). As such, these cases are commonly referred to as FTLD-FUS. Here, we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Unexpectedly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15), rather than of FUS itself. The filament fold is formed from residues 7 to 99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, who also showed changes associated with amyotrophic lateral sclerosis (ALS), suggesting that TAF15 proteinopathy may underlie a disease spectrum of FTLD and ALS. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
2023-12-07 | PXD044821 | Pride
Project description:TAF15, an RNA binding protein was recently implicated in Amyotrophic Lateral Sclerosis (ALS). ALS is a fatal neurodegenerative disease. We report the identification of the conserved neuronal RNA targets of TAF15 and the assessment of the impact of TAF15 depletion on the neuronal transcriptome. Our study uncovers regulation of splicing of sets of neuronal RNAs encoding proteins with essential roles in synaptic activities including glutamergic receptors such as zeta-1 subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor (Grin1). Identification of TAF15 neuronal targets using normal human brain samples and mouse neurons. Mouse background: E14Tg2a.4 wildtype cells derived from 129P2/OlaHsd.
2013-01-24 | E-GEOD-43294 | biostudies-arrayexpress
Project description:TAF15, an RNA binding protein was recently implicated in Amyotrophic Lateral Sclerosis (ALS). ALS is a fatal neurodegenerative disease. We report the identification of the conserved neuronal RNA targets of TAF15 and the assessment of the impact of TAF15 depletion on the neuronal transcriptome. Our study uncovers regulation of splicing of sets of neuronal RNAs encoding proteins with essential roles in synaptic activities including glutamergic receptors such as zeta-1 subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor (Grin1).
2013-01-24 | GSE43294 | GEO
Project description:TAF15, a DNA and RNA-binding protein primarily localized in the nucleus, has been reported to be associated with the aging process and neurodegenerative diseases accompanied by cognitive decline. However, its role in regulating learning and memory remains unclear. Here, we discovered that TAF15 accumulates in the hippocampus of aged mice, and TAF15 overexpressing in hippocampal neurons led to spatial learning and memory impairments in young mice. These finding are further supported by the significant reduction of dendritic spines density and synaptic proteins level. Further studies revealed that overexpression of TAF15 is likely to reduce the number of dendritic spines by inhibiting the expression of Npas4 (among the most rapidly induced immediate-early genes) and its target gene Nptx2. Notably, the expression of Npas4 and Nptx2 in the hippocampus of aged mice is also downregulated. Additionally, we demonstrated that TAF15 binds to the core promoter of Npas4 gene and inhibits its transcription, and neuronal depolarization induces the dissociation of TAF15 from Npas4 promoter. Together, these findings uncover a direct role of TAF15 in regulating spatial learning and memory formation, which may provide new insights into aging-related cognitive deficits.
2024-12-18 | GSE244954 | GEO
Project description:TDP-43, FUS, and TAF15 are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We integrate CLIP-seq and RNA Bind-N-Seq technologies to discover that TAF15 binds to ~4,900 RNAs enriched for GGUA motifs. In the mouse brain, TAF15 and FUS, but not TDP-43, exhibit strikingly similar RNA binding profiles, yet they alter the expression of distinct mRNA populations upon their individual depletions. TAF15 has a minimal role in alternative splicing and instead affects RNA turnover, consistent with an enrichment of TAF15 binding sites in 3â untranslated regions. In human stem cell-derived motor neurons, loss of both TAF15 and FUS affected mRNAs distinct from those altered by loss of either protein alone, revealing redundant roles for TAF15 and FUS in maintaining mRNA levels. Furthermore, concomitant rather than individual depletion of TAF15 and FUS more closely resembles RNA profiles of motor neurons derived from FUS R521G ALS patients or from late-stage, sporadic ALS patients. Our study reveals convergent and divergent mechanisms by which FUS, TAF15 and TDP-43 affects RNA metabolism in neurological disease. RNA-seq, CLIP-seq and arrays in mouse and human against TAF15 knockdowns This Series represents array sample(s).
2016-07-05 | E-GEOD-77699 | biostudies-arrayexpress
Project description:TDP-43, FUS, and TAF15 are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We integrate CLIP-seq and RNA Bind-N-Seq technologies to discover that TAF15 binds to ~4,900 RNAs enriched for GGUA motifs. In the mouse brain, TAF15 and FUS, but not TDP-43, exhibit strikingly similar RNA binding profiles, yet they alter the expression of distinct mRNA populations upon their individual depletions. TAF15 has a minimal role in alternative splicing and instead affects RNA turnover, consistent with an enrichment of TAF15 binding sites in 3’ untranslated regions. In human stem cell-derived motor neurons, loss of both TAF15 and FUS affected mRNAs distinct from those altered by loss of either protein alone, revealing redundant roles for TAF15 and FUS in maintaining mRNA levels. Furthermore, concomitant rather than individual depletion of TAF15 and FUS more closely resembles RNA profiles of motor neurons derived from FUS R521G ALS patients or from late-stage, sporadic ALS patients. Our study reveals convergent and divergent mechanisms by which FUS, TAF15 and TDP-43 affects RNA metabolism in neurological disease.
2016-07-05 | GSE77699 | GEO