Affinage

PRPF40B

Pre-mRNA-processing factor 40 homolog B · UniProt Q6NWY9

Length
871 aa
Mass
99.4 kDa
Annotated
2026-06-10
19 papers in source corpus 3 papers cited in narrative 8 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRPF40B is a nuclear splicing factor that regulates alternative pre-mRNA splice site selection and controls splicing-dependent cell fate decisions (PMID:25605964, PMID:31088860). It directly binds the early spliceosome assembly factor SF1 and associates with U2AF65, colocalizing with these factors in nuclear speckles, where its enrichment is coupled to its splicing-regulatory function (PMID:25605964). Genome-wide loss-of-function defines PRPF40B as predominantly a splicing repressor: its depletion produces a net increase in exon inclusion across hundreds of events, and the regulated targets are enriched for weak 5' splice sites and A-rich downstream intronic motifs, indicating recognition of suboptimal splice sites (PMID:31088860). Through this activity PRPF40B shapes specific cell-fate programs — it represses Fas/CD95 splicing such that its loss raises Fas surface expression and promotes apoptosis (PMID:25605964), directs the NTRK2 isoform balance toward full-length TRKB (TRKB-FL) over the truncated TRKB-T1 form to support neuronal differentiation and synaptic plasticity gene expression (PMID:41360765), and restrains a KLF1-associated transcriptional program linked to iron metabolism and hypoxia in myeloid cells (PMID:31088860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2015 High

    Establishing PRPF40B's molecular partners and subcellular context was needed to place it within spliceosome assembly; demonstrating direct SF1 binding, U2AF65 association, and nuclear speckle localization positioned it as a bona fide splice-site regulator.

    Evidence Co-immunoprecipitation, direct interaction assays, immunofluorescence colocalization, and minigene splicing reporters with siRNA knockdown

    PMID:25605964

    Open questions at the time
    • Structural basis of the SF1 interaction not resolved
    • Whether U2AF65 association is direct or bridged is undefined
    • Localization tied to function but not tested by FRAP or fractionation
  2. 2015 Medium

    Connecting PRPF40B to a cellular outcome showed that its splicing activity is functionally consequential; depletion raised Fas/CD95 receptor levels and promoted apoptosis, with weak splice sites and exonic sequences required at the Fas locus.

    Evidence siRNA knockdown, splicing minigene reporters, flow cytometry for Fas, and apoptosis assays

    PMID:25605964

    Open questions at the time
    • Direct binding of PRPF40B to the Fas pre-mRNA not demonstrated
    • Single lab and single cellular context
  3. 2019 High

    The directionality and sequence logic of PRPF40B regulation were unknown; transcriptome-wide knockout showed it is primarily a repressor of exon inclusion that recognizes weak 5' splice sites and A-rich downstream intronic motifs.

    Evidence CRISPR/Cas9 knockout in K562 with RNA-seq and rescue using wild-type and MDS mutant alleles

    PMID:31088860

    Open questions at the time
    • Direct RNA-binding map (e.g., CLIP) not generated
    • Mechanism by which weak splice sites are repressed not resolved
    • Functional impact of MDS mutant alleles on splicing outcomes only partly characterized
  4. 2019 Medium

    Whether PRPF40B loss had broader gene-expression consequences was untested; knockout induced a KLF1 signature spanning iron metabolism and hypoxia-related pathways, implicating it in myeloid transcriptional programs.

    Evidence CRISPR/Cas9 knockout with RNA-seq gene expression and rescue analysis

    PMID:31088860

    Open questions at the time
    • No direct molecular mechanism linking PRPF40B to hypoxia gene repression
    • Whether the effect is splicing-driven or secondary is unresolved
  5. 2025 Medium

    A developmental role for PRPF40B splicing control was unknown; it was shown to favor the TRKB-FL over TRKB-T1 isoform of NTRK2, with silencing impairing neuronal differentiation and synaptic plasticity gene expression in vitro and in vivo.

    Evidence siRNA knockdown, in vitro neuronal differentiation, in vivo embryogenesis models, and RT-PCR/RNA-seq isoform quantification

    PMID:41360765

    Open questions at the time
    • Direct binding of PRPF40B to NTRK2 pre-mRNA not shown
    • Single lab
    • Mechanistic link between isoform switch and the differentiation phenotype not fully dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how human PRPF40B associates with the spliceosome relative to its yeast ortholog Prp40 and whether its regulation is genuinely cotranscriptional.
  • Whether human PRPF40B is a U1 snRNP component is inferred, not directly tested
  • Cotranscriptional coupling inferred from sequence features, not measured directly
  • No direct RNA-binding or recruitment mechanism established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 1
Localization
GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
SF1U2AF65

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 PRPF40B directly interacts with the splicing factor SF1 and associates with U2AF65, colocalizing with these factors in nuclear speckles, and modulates alternative pre-mRNA splice site selection in vivo. Co-immunoprecipitation, direct interaction assays, colocalization by immunofluorescence, splicing reporter minigene assays, siRNA knockdown RNA (New York, N.Y.) High 25605964
2015 PRPF40B is highly enriched in nuclear speckles, displaying localization behavior similar to established splicing factors, and this localization is functionally coupled to its role in splice site regulation. Immunofluorescence microscopy and colocalization with splicing factor markers RNA (New York, N.Y.) Medium 25605964
2015 PRPF40B depletion increases Fas/CD95 receptor number and promotes cell apoptosis, demonstrating that PRPF40B regulates alternative splicing of apoptotic genes to control cell survival; weak 5' and 3' splice sites and exonic sequences are required for PRPF40B function at the Fas locus. siRNA knockdown, splicing reporter minigene assays, flow cytometry for Fas surface expression, apoptosis assays RNA (New York, N.Y.) Medium 25605964
2019 PRPF40B knockout in K562 cells causes a net increase in exon inclusion among hundreds of alternative splicing events, indicating that PRPF40B primarily acts as a splicing repressor; regulated events are enriched for A-rich downstream intronic motifs and weak 5' splice sites. CRISPR/Cas9 knockout, RNA-seq, rescue with wild-type and MDS mutant alleles RNA (New York, N.Y.) High 31088860
2019 Loss of PRPF40B in K562 cells induces a KLF1 transcriptional signature involving iron metabolism and hypoxia-related pathways (including cholesterol biosynthesis and Akt/MAPK signaling), suggesting PRPF40B represses hypoxia-associated gene expression in myeloid cells. CRISPR/Cas9 knockout, RNA-seq gene expression analysis, rescue experiments RNA (New York, N.Y.) Medium 31088860
2019 PRPF40B-regulated alternative splicing events are likely cotranscriptional, consistent with its ortholog Prp40 being part of the U1 snRNP. RNA-seq analysis of splice-site features in PRPF40B KO cells RNA (New York, N.Y.) Low 31088860
2025 PRPF40B promotes production of the full-length TRKB (TRKB-FL) isoform over the truncated TRKB-T1 isoform during neuronal differentiation by regulating alternative splicing of NTRK2; silencing PRPF40B shifts the balance toward TRKB-T1 and impairs neuronal differentiation and synaptic plasticity gene expression both in vitro and in vivo during early embryogenesis. siRNA knockdown, in vitro neuronal differentiation assays, in vivo embryogenesis models, RT-PCR/RNA-seq for isoform quantification Cell death & disease Medium 41360765
2025 Human PRPF40B (and its paralog PRPF40A) are not integral components of U1 snRNP, in contrast to their yeast ortholog Prp40 which is stably associated with U1 snRNP; instead, human PRPF40B functions as an alternative splicing factor. Comparative biochemical analysis and cryo-EM/structural context from yeast Prp40 studies; functional annotation from published literature reviewed in the context of yeast experiments bioRxivpreprint Low

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Interaction of the hydrogenase accessory protein HypC with HycE, the large subunit of Escherichia coli hydrogenase 3 during enzyme maturation. Biochemistry 90 9485446
2004 The complex between hydrogenase-maturation proteins HypC and HypD is an intermediate in the supply of cyanide to the active site iron of [NiFe]-hydrogenases. Journal of molecular biology 88 15504408
2002 Maturation of [NiFe]-hydrogenases in Escherichia coli: the HypC cycle. Journal of molecular biology 79 12441107
2000 Analysis of the HypC-hycE complex, a key intermediate in the assembly of the metal center of the Escherichia coli hydrogenase 3. The Journal of biological chemistry 73 10783387
2001 Interplay between the specific chaperone-like proteins HybG and HypC in maturation of hydrogenases 1, 2, and 3 from Escherichia coli. Journal of bacteriology 54 11292801
2010 HypC, the anthrone oxidase involved in aflatoxin biosynthesis. Applied and environmental microbiology 45 20348292
2015 Prp40 pre-mRNA processing factor 40 homolog B (PRPF40B) associates with SF1 and U2AF65 and modulates alternative pre-mRNA splicing in vivo. RNA (New York, N.Y.) 30 25605964
2004 Requirement of hydD, hydE, hypC and hypE genes for hydrogenase activity in Helicobacter pylori. Microbial pathogenesis 25 14726233
2009 CalA, a cyanobacterial AbrB protein, interacts with the upstream region of hypC and acts as a repressor of its transcription in the cyanobacterium Nostoc sp. strain PCC 7120. Applied and environmental microbiology 19 20023111
2019 Human PRPF40B regulates hundreds of alternative splicing targets and represses a hypoxia expression signature. RNA (New York, N.Y.) 17 31088860
2015 Heterologous complementation studies in Escherichia coli with the Hyp accessory protein machinery from Chloroflexi provide insight into [NiFe]-hydrogenase large subunit recognition by the HypC protein family. Microbiology (Reading, England) 9 26364315
2007 Solution structure of Escherichia coli HypC. Biochemical and biophysical research communications 9 17669368
1997 The sequences of hypF, hypC and hypD complete the hyp gene cluster required for hydrogenase activity in Bradyrhizobium japonicum. Gene 8 9358044
2022 [NiFe] Hydrogenase Accessory Proteins HypB-HypC Accelerate Proton Conversion to Enhance the Acid Resistance and d-Lactic Acid Production of Escherichia coli. ACS synthetic biology 6 35271275
2014 Maturation of Rhizobium leguminosarum hydrogenase in the presence of oxygen requires the interaction of the chaperone HypC and the scaffolding protein HupK. The Journal of biological chemistry 5 24942742
2013 Computational study of the Fe(CN)2CO cofactor and its binding to HypC protein. The journal of physical chemistry. B 5 24094065
2007 Crystallization and preliminary X-ray crystallographic studies of the [NiFe] hydrogenase maturation proteins HypC and HypD. Acta crystallographica. Section F, Structural biology and crystallization communications 5 17554182
2018 The Extended C-Terminal α-Helix of the HypC Chaperone Restricts Recognition of Large Subunit Precursors by the Hyp-Scaffold Machinery during [NiFe]-Hydrogenase Maturation in Escherichia coli. Journal of molecular microbiology and biotechnology 2 29996137
2025 Regulation of NTRK2 alternative splicing by PRPF40B controls neural differentiation and synaptic plasticity. Cell death & disease 1 41360765

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