Affinage

CPSF6

Cleavage and polyadenylation specificity factor subunit 6 · UniProt Q16630

Length
551 aa
Mass
59.2 kDa
Annotated
2026-06-09
80 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CPSF6 is a subunit of the cleavage factor Im (CFIm) complex that governs mRNA alternative polyadenylation (APA) genome-wide by activating enhancer-containing poly(A) sites, with its arginine/serine-like domain (RSLD) docking onto an RS-like region of the CPSF/Fip1 3'-processing machinery in a phosphorylation-sensitive manner (PMID:29276085). Most cellular CPSF6 resides in CFIm with CPSF5 and CPSF7 (PMID:26994143), and its APA output is set not merely by abundance but by RSLD-dependent liquid-liquid phase separation, which CLK2 phosphorylation dissolves to shift usage toward proximal poly(A) sites and promote proliferation (PMID:37777964). Nuclear import of CPSF6 is mediated by TNPO3 binding to the RSLD, an interaction resolved structurally and dispensable for, yet inhibited by, RSLD hyperphosphorylation (PMID:30916345). Through this APA activity CPSF6 shapes diverse programs including innate antiviral gene expression, where reduced CPSF6 shortens 3' UTRs of immune transcripts to enhance type I IFN signaling (PMID:38416782, PMID:41385587), and is itself a degradation target of the MAVS-activated E3 ligase SYVN1, which K48-polyubiquitinates CPSF6 to remodel the APA transcriptome during antiviral responses (PMID:39951376). CPSF6 is a central host cofactor for HIV-1: nuclear CPSF6 binds a conserved pocket in assembled HIV-1 capsid (CA) hexamers at the NTD-CTD interface (PMID:22956906, PMID:25518861), and this engagement is spatially gated by cytoplasmic cyclophilin A, whose prior binding prevents premature capsid-CPSF6 association (PMID:33758083, PMID:40013779). CPSF6 licenses capsid trafficking through the nuclear pore and interior, undergoes capsid-scaffolded condensation at nuclear speckles via its FG and mixed-charge domains (PMID:39258548, PMID:41493399), directs viral DNA integration into gene-dense, transcriptionally active speckle-associated chromatin domains, and directly stimulates preintegration complex integration activity (PMID:26858452, PMID:30173955, PMID:40202316). Cytoplasmic mislocalization or truncation of CPSF6 instead aberrantly stabilizes or disrupts the incoming capsid and blocks infection (PMID:23622145, PMID:29643241). Chromosomal rearrangements fusing CPSF6 to FGFR1 or RARG drive myeloproliferative and acute myeloid leukemias, the latter through recruitment of HDAC3 to repress myeloid differentiation genes (PMID:39805830, PMID:18205209).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 Medium

    Established that CPSF6, as a CFIm subunit, directs tissue-specific alternative polyadenylation, providing the first functional context for the protein in RNA 3'-end processing.

    Evidence Expression and CFIm binding-site analysis in mouse male germ cells

    PMID:18032416

    Open questions at the time
    • No reconstitution of CFIm-directed APA in vitro
    • Causal role in spermatogenesis not tested by loss-of-function
  2. 2008 Medium

    Identified CPSF6 as a fusion partner in a myeloproliferative rearrangement, framing its N-terminal domain as an oligomerization module that can constitutively activate a partner kinase.

    Evidence Cytogenetics and breakpoint cloning of CPSF6-FGFR1 in an 8p11 syndrome patient

    PMID:18205209

    Open questions at the time
    • No in vitro kinase activation assay
    • Oligomerization mechanism inferred, not measured
  3. 2012 High

    Defined the structural basis of CPSF6 recognition of HIV-1, revealing a conserved capsid interface and linking capsid binding to dependence on nuclear-entry cofactors.

    Evidence X-ray crystallography, mutagenesis, and infectivity assays with truncated CPSF6-358

    PMID:22956906

    Open questions at the time
    • Did not establish whether assembled lattice versus monomeric CA is the target
    • Physiological role of full-length CPSF6 in infection unaddressed
  4. 2013 High

    Resolved the cell-biological logic of CPSF6 in HIV-1 by showing TNPO3 acts through CPSF6 nuclear import and that cytoplasmic CPSF6 is the effector that stabilizes the capsid and blocks nuclear entry.

    Evidence TNPO3/CPSF6 knockdown, localization mutants, epistatic rescue, and fate-of-capsid assays in two independent labs

    PMID:23414560 PMID:23622145 PMID:23658440

    Open questions at the time
    • Mechanism by which cytoplasmic CPSF6 stabilizes the core unresolved
    • Distinct truncation phenotypes (uncoating acceleration vs. stabilization) not unified
  5. 2014 High

    Demonstrated that the assembled capsid hexamer lattice, not isolated CA, is the high-affinity CPSF6 target, defining a preformed druggable pocket shared with PF74.

    Evidence Quantitative binding and crystallography of CPSF6/PF74-CA hexamer complexes

    PMID:25518861

    Open questions at the time
    • Stoichiometry of CPSF6 on intact cores in cells not determined
    • Link between lattice binding and downstream trafficking not yet established
  6. 2016 High

    Established CPSF6 as the dominant determinant of HIV-1 integration into euchromatin, mechanistically separable from LEDGF/p75 and independent of its CFIm partners.

    Evidence CPSF6/LEDGF knockouts with binding-deficient complementation, CFIm-disrupting mutants, and integration site sequencing

    PMID:26858452 PMID:26994143

    Open questions at the time
    • How capsid-bound CPSF6 selects active chromatin not defined
    • Role of speckle association not yet identified
  7. 2017 High

    Defined CFIm/CPSF6 as an enhancer-dependent activator of 3' processing and identified the RSLD-Fip1 interaction as the phosphorylation-regulated molecular contact driving distal poly(A) site activation.

    Evidence In vitro RS-domain binding assays, RSLD mutagenesis, phosphorylation analysis, and global APA profiling

    PMID:29276085

    Open questions at the time
    • Kinases controlling RSLD phosphorylation in vivo not identified here
    • Connection to phase behavior not yet appreciated
  8. 2018 High

    Showed CPSF6 is a master regulator of HIV-1 intranuclear localization, routing complexes to the nuclear interior and away from heterochromatin at the lamina.

    Evidence Live-cell and fixed imaging with CPSF6 knockout/complementation and integration site sequencing

    PMID:30173955

    Open questions at the time
    • Molecular basis of interior targeting not defined
    • Relationship to nuclear speckles not yet shown
  9. 2019 High

    Provided structural and spatial detail for CPSF6 in nuclear entry, defining RSLD-TNPO3 recognition and showing CPSF6 acts at the nuclear basket after Nup153 to license pore passage.

    Evidence Crystal structure of RSLD-TNPO3, mutagenesis, STED microscopy, and primary macrophage infection

    PMID:30672737 PMID:30916345

    Open questions at the time
    • Whether CPSF6 condensation participates in pore passage not addressed
    • Ordering of Nup153/CPSF6 handoff inferred
  10. 2020 High

    Established that capsid-CPSF6 interaction is a primate lentivirus-specific adaptation for targeting speckle-associated chromatin domains, and identified post-transcriptional control of CPSF6 by miR-125b during infection.

    Evidence Large-scale comparative integration mapping with KO/KD and binding assays; luciferase reporter, RNA pulldown, and seed mutagenesis for miR-125b

    PMID:32152226 PMID:32994325

    Open questions at the time
    • How SPAD targeting is physically achieved still open
    • miR-125b regulation single-lab
  11. 2021 High

    Showed HIV-1 induces higher-order CPSF6 assemblies that bind and disrupt capsids, and that CypA binding gates premature cytoplasmic engagement of CPSF6.

    Evidence Live-cell co-trafficking imaging, in vitro capsid disruption, and CypA inhibition; plus APA/NQO1 oncogenic profiling in HCC

    PMID:33648552 PMID:33758083

    Open questions at the time
    • Physical nature of higher-order CPSF6 not defined here
    • Spatial separation of CypA/CPSF6 not yet tested directly
  12. 2023 High

    Unified CPSF6 function around liquid-liquid phase separation: RSLD-driven LLPS sets APA output and CLK2 phosphorylation dissolves it, while capsid-scaffolded CPSF6/CPSF5 condensates at nuclear speckles are required for productive HIV-1 infection.

    Evidence In vitro LLPS and CLK2 kinase assays with APA profiling; hexanediol/osmotic disruption of CPSF6 condensates with capsid mutant controls; circadian temperature-compensation KD

    PMID:37379316 PMID:37414787 PMID:37777964

    Open questions at the time
    • Whether the same condensates serve APA and HIV-1 integration unresolved
    • In vivo regulation of CLK2-CPSF6 axis untested
  13. 2024 High

    Dissected the domain requirements for CPSF6 condensation in HIV-1 (FG domain for puncta/core binding, MCD for LLPS-dependent intranuclear penetration) and placed CPSF6 in antiviral circuits via SYVN1-mediated K48 degradation and APA-driven IFN enhancement.

    Evidence Domain-deletion and heterologous-MCD rescue with integration analysis; FG/SRRM2 imaging; SYVN1 ubiquitination assays with MAVS/NUP153 epistasis; immune-gene APA profiling

    PMID:38416782 PMID:39258548 PMID:39951376 PMID:41493399

    Open questions at the time
    • How condensation mechanically promotes pore-to-interior trafficking unresolved
    • Generality of SYVN1 regulation across cell types not established
  14. 2025 High

    Established that CPSF6 directly stimulates PIC integration activity, that its NLS governs intranuclear SPAD trafficking beyond import, and that CPSF6 loss reprograms immune APA to alter HIV-1 permissivity; also defined the CPSF6-RARG/HDAC3 leukemic mechanism.

    Evidence PIC in vitro integration with recombinant add-back; heterologous NLS chimeras with SPAD imaging; CypA/CPSF6 sequential-binding epistasis; primary CD4+ T-cell KO APA/infectivity; Co-IP and HDAC inhibitor leukemia model

    PMID:39805830 PMID:39823525 PMID:40013779 PMID:40202316 PMID:41385587

    Open questions at the time
    • Biochemical mechanism by which CPSF6 stimulates integration unknown
    • Whether SPAD-targeting and PIC stimulation are separable activities unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether CPSF6's APA-regulatory phase-separation activity and its HIV-1 integration-targeting condensate function share a common biophysical mechanism, and how the same condensate properties are partitioned between physiological 3'-processing and capsid-driven chromatin targeting.
  • No structure of capsid-CPSF6 condensates at chromatin
  • Direct biochemical activity of CPSF6 on PIC integration undefined
  • Interplay between phosphorylation, LLPS, and APA versus HIV-1 functions not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0060090 molecular adaptor activity 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3
Partners
CLK2CPSF5CPSF7FIP1L1FXR1HDAC3SYVN1TNPO3
Complex memberships
CFIm (cleavage factor Im)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 CPSF6 binds to a novel protein-protein interface in the N-terminal domain of HIV-1 capsid (CA), defined by X-ray crystallography; this interface is conserved across lentiviruses and is accessible in the hexameric lattice. A truncated cytosolic form, CPSF6-358, restricts HIV-1 by binding this interface, and mutations that abolish CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. X-ray crystallography, mutagenesis, infectivity assays, binding assays PLoS pathogens High 22956906
2014 CPSF6 binds the assembled HIV-1 CA hexamer at the NTD-CTD interface pocket with at least 10-fold higher affinity than non-assembled CA or isolated domains; crystal structure of PF74 in complex with the hexamer shows CPSF6 and the drug bind the same preformed pocket, indicating the assembled capsid lattice is the principal binding target. Biochemical binding assays, X-ray crystallography of CA hexamer complexes Proceedings of the National Academy of Sciences of the United States of America High 25518861
2013 TNPO3 promotes HIV-1 infectivity indirectly by importing CPSF6 into the nucleus; when TNPO3 is knocked down, CPSF6 accumulates in the cytoplasm and abnormally stabilizes the HIV-1 CA core, blocking infection. Mislocalization of CPSF6 to the cytoplasm (via NLS deletion or nuclear export signal fusion) phenocopies TNPO3 knockdown, while targeting CPSF6 to the nucleus with a heterologous NLS rescues infection. Sensitivity of 27 CA mutants to TNPO3 knockdown correlates strongly with sensitivity to CPSF6-358 inhibition (R²=0.883). TNPO3 knockdown, CPSF6 localization mutants, fate-of-capsid assays, 2-LTR circle quantification, correlation of CA mutant panels Retrovirology High 23414560
2013 Cytoplasmic full-length CPSF6 (overexpressed without NLS) blocks HIV-1 nuclear import and enhances stability of the HIV-1 core; simultaneous depletion of both TNPO3 and CPSF6 rescues HIV-1 infection that is blocked by TNPO3 depletion alone, establishing CPSF6 as the effector of TNPO3-dependent restriction. siRNA depletion, cytoplasmic CPSF6 overexpression, fate-of-capsid assay, infectivity rescue Retrovirology High 23622145
2013 A carboxy-terminally truncated CPSF6 variant (hCPSF6-375, lacking exon 6) aberrantly accelerates HIV-1 capsid disassembly in target cells and inhibits viral cDNA synthesis; residues encoded by exon 6 are responsible for the cDNA synthesis block. This is mechanistically distinct from CPSF6-358, which does not accelerate uncoating. cDNA expression cloning, ganciclovir-mediated selection, mutational analysis, capsid disassembly assay, viral cDNA quantification Journal of virology Medium 23658440
2016 CPSF6 knockout preferentially decreases HIV-1 integration into transcriptionally active genes, spliced genes, and euchromatic regions; capsid-binding-deficient CPSF6 fails to rescue integration site distribution. Dual knockout of CPSF6 and LEDGF/p75 showed CPSF6 plays a more dominant role in directing integration to euchromatin, while LEDGF/p75 mainly directs positional targeting within gene bodies, establishing two mechanistically distinct pathways. CPSF6 knockout, LEDGF/p75 depletion, integration site sequencing, CPSF6 complementation with capsid-binding mutant Proceedings of the National Academy of Sciences of the United States of America High 26858452
2016 The majority of cellular CPSF6 is incorporated into the CFIm complex (with CPSF5/CFIm25 and CPSF7); HIV-1 capsid recruits the CFIm complex in a CPSF6-dependent manner. However, CPSF6 incorporation into CFIm is not required for its ability to direct HIV-1 integration into genes; CPSF6 alone, independent of its CFIm partners CPSF5 and CPSF7, controls the key molecular interactions for PIC trafficking to active chromatin. Co-immunoprecipitation, CFIm-disrupting CPSF6 mutants, integration site analysis, virological assays The Journal of biological chemistry High 26994143
2017 CFIm (CPSF6/CFIm68 and CPSF5/CFIm59 subunits) functions as an enhancer-dependent activator of mRNA 3' processing; CFIm regulates global alternative polyadenylation by binding and activating enhancer-containing poly(A) sites. The RS domains of CFIm68/59 bind specifically to an RS-like region in CPSF/Fip1, and this interaction is inhibited by hyper-phosphorylation of CFIm68/59. Biochemical binding assays, APA profiling, RS-domain mutagenesis, phosphorylation analysis Molecular cell High 29276085
2018 Capsid-CPSF6 interaction licenses HIV-1 trafficking throughout the nuclear interior; loss of CPSF6 interaction dramatically shifts virus localization to the nuclear periphery and redirects integration into transcriptionally repressed lamina-associated heterochromatin, while loss of LEDGF/p75 does not significantly affect intranuclear HIV-1 localization. CPSF6 serves as a master regulator of HIV-1 intranuclear localization. Live-cell and fixed imaging of HIV-1 nuclear localization, CPSF6 knockout/complementation, integration site sequencing Cell host & microbe High 30173955
2018 Truncated CPSF6-358 forms higher-order oligomeric complexes that bind assembled wild-type HIV-1 CA tubes but not CA tubes bearing a CPSF6 binding-site mutation; binding physically disrupts the tubular capsid assemblies. In cells, CPSF6-358 forms cytoplasmic puncta upon HIV-1 infection, leading to capsid permeabilization in a capsid-binding-dependent manner. In vitro binding with purified CPSF6-358 oligomers and CA tubes, transmission electron microscopy, live- and fixed-cell imaging, capsid permeabilization assay Journal of virology High 29643241
2019 CPSF6 is strongly recruited to nuclear HIV-1 replication complexes (but absent from cytoplasmic RTC/PIC) in primary human macrophages. Depletion of CPSF6 or lack of CPSF6 binding causes accumulation of HIV-1 subviral complexes at the nuclear envelope. STED microscopy showed that CPSF6-binding-deficient complexes are retained inside the nuclear pore in a CA-multimer-dependent manner, with CPSF6 clustering adjacent to the nuclear basket, suggesting consecutive Nup153/CPSF6 binding to the hexameric lattice mediates nuclear entry. Quantitative fluorescence microscopy, CPSF6 depletion, STED super-resolution microscopy, primary macrophage infection eLife High 30672737
2019 The arginine/serine-like domain (RSLD) of CPSF6 mediates TNPO3 binding and is critical for CPSF6 nuclear import; the crystal structure of the RSLD-TNPO3 complex identified specific interaction residues confirmed by mutagenesis. RSLD phosphorylation is not required for TNPO3 binding or nuclear import, but a hyperphosphorylated mimetic mutant fails to bind TNPO3 and mislocalizes to the cytoplasm. Hypophosphorylated CPSF6 extends 3' UTRs similarly to depletion of CFIIm components. Crystal structure of RSLD-TNPO3 complex, mutagenesis of interaction residues, nuclear import assays, APA profiling Nucleic acids research High 30916345
2020 CPSF6 is post-transcriptionally regulated by the cellular microRNA miR-125b, which binds the 3'UTR of CPSF6 mRNA; miR-125b and CPSF6 levels are inversely correlated. Pulldown experiments show miR-125b physically interacts with CPSF6 3'UTR. HIV-1 infection down-regulates miR-125b (dependent on reverse transcription but not integration), concurrently upregulating CPSF6. miRNA knockdown/overexpression, luciferase reporter with CPSF6 3'UTR, seed-sequence mutagenesis, RNA pulldown The Journal of biological chemistry Medium 32152226
2020 Primate lentiviral capsid proteins have evolved to interact with CPSF6 to target speckle-associated domains (SPADs) for integration; CPSF6 depletion specifically counteracts SPAD integration targeting by primate lentiviruses but not nonprimate lentiviruses, which also fail to appreciably interact with CPSF6. This demonstrates that CPSF6-capsid interaction is a primate lentivirus-specific evolutionary adaptation for integration into gene-dense, transcriptionally active chromatin. Integration site mapping (>5 million sites), CPSF6 KO/KD, LEDGF/p75 KO, Co-IP of CPSF6 with lentiviral capsids mBio High 32994325
2021 HIV-1 infection induces higher-order CPSF6 formation in cells, and capsid-CPSF6 complexes co-traffic on microtubules. Higher-order CPSF6 complexes bind and physically disrupt HIV-1 capsid assemblies in vitro. Disruption of CypA binding to capsid leads to increased CPSF6 binding and altered capsid trafficking; CypA prevents HIV-1 capsid from prematurely engaging cytoplasmic CPSF6. Live-cell imaging of capsid-CPSF6 co-trafficking, in vitro capsid binding/disruption assays, CypA inhibition, infectivity assays mBio High 33758083
2023 CPSF6 undergoes liquid-liquid phase separation (LLPS) in vitro; its arginine/serine-like domain (RSLD) controls LLPS activity. CLK2 kinase phosphorylates the RSLD to disrupt CPSF6 LLPS, reducing CPSF6 condensates and leading to preferential proximal poly(A) site usage (3' UTR shortening) and accelerated cell proliferation. CPSF6 LLPS, rather than expression level per se, determines APA regulation in cancer cells. In vitro LLPS assay, CLK2 kinase assay, RSLD mutagenesis, APA profiling, cell proliferation assays Cell reports High 37777964
2023 Upon HIV-1 nuclear entry, CPSF6 and CPSF5 (but not CPSF7) translocate from paraspeckles to nuclear speckles, forming biomolecular condensates. Neither HIV-1 integration nor reverse transcription is required for condensate formation; condensates are disrupted by osmotic stress and 1,6-hexanediol. Preventing condensate formation inhibits WT HIV-1 but not capsid mutants (N74D, A77V) that do not engage CPSF6, establishing that CPSF6 condensate formation is important for productive WT HIV-1 infection. Fluorescence microscopy of CPSF6 puncta, osmotic stress/hexanediol condensate disruption, integration-deficient and genome-free virus controls Scientific reports High 37414787
2024 CPSF6 mixed-charge domain (MCD) is required for LLPS-dependent higher-order capsid binding and co-aggregation in vitro and in cells; MCD-deleted CPSF6 supports normal capsid binding affinity but fails to promote post-nuclear entry virus localization (PICs arrest at nuclear rim). Heterologous MCDs, but not Arg-Ser domains from SR proteins, can substitute for CPSF6 MCD in HIV-1 infection, and appending MCD to a heterologous capsid-binding protein partially restores nuclear penetration and integration targeting in CPSF6 KO cells. In vitro LLPS assay, capsid co-aggregation, domain-swap rescue experiments, imaging of intranuclear localization, integration site analysis in KO cells Nucleic acids research High 39258548
2024 SYVN1 E3 ligase, whose nuclear import is triggered by MAVS signaling upon vesicular stomatitis virus infection (via NUP153), catalyzes K48-linked polyubiquitination of CPSF6, leading to proteasomal degradation of CPSF6, transcriptome-wide APA changes, and antiviral effects in macrophages. Co-IP, ubiquitination assay, proteasome inhibitor experiments, MAVS pathway perturbation, APA sequencing Cell reports High 39951376
2025 Sequential binding of CypA (cytoplasm) then CPSF6 (nucleus) to HIV-1 capsid is required for optimal nuclear entry and integration targeting; a capsid mutant with increased CypA affinity shows reduced nuclear entry and mislocalized integration, but disrupting CypA binding restores these in a CPSF6-dependent manner. Nuclear relocation of CypA fails to rescue mutant HIV-1, confirming spatial separation of CypA and CPSF6 binding is mechanistically critical. CypA binding affinity mutants, CPSF6-dependent rescue assays, nuclear entry quantification, integration site analysis, CypA nuclear relocalization mBio High 40013779
2025 CPSF6-RARG fusion protein (from t(1;12) chromosomal rearrangement in AML) interacts with histone deacetylase 3 (HDAC3) to suppress myeloid differentiation genes including PU.1; disrupting the CR-HDAC3 interaction restores PU.1 expression and myeloid differentiation, and HDAC inhibitors suppress CR-driven leukemia in vitro and in vivo. Co-IP of CPSF6-RARG with HDAC3, domain-disruption mutants, gene expression analysis, HDAC inhibitor treatment, mouse leukemia model Nature communications High 39805830
2025 CPSF6 directly promotes HIV-1 preintegration complex (PIC) activity; PICs extracted from CPSF6-depleted or capsid-binding-deficient CPSF6 mutant cells show significantly lower viral DNA integration activity in vitro. Adding purified recombinant CPSF6 restores integration activity of PICs from CPSF6-mutant cells. Disruption of CPSF6-CA binding in cells reduces viral DNA integration and redirects integration away from gene-dense chromatin, independent of effects on reverse transcription or nuclear entry. PIC extraction and in vitro integration assay, recombinant CPSF6 add-back, integration site sequencing, reverse transcription/nuclear entry controls Journal of virology High 40202316
2025 The NLS of CPSF6 governs post-nuclear import steps of HIV-1 infection; some NLS chimeras drive CPSF6-358 into the nucleus but fail to support efficient HIV-1 infection. HIV-1 still enters the nucleus in these cells but fails to traffic to speckle-associated domains (SPADs) and fails to integrate efficiently, demonstrating that CPSF6's NLS facilitates intranuclear trafficking and SPAD targeting rather than merely nuclear import per se. Heterologous NLS rescue of CPSF6-358, HIV-1 nuclear entry quantification, integration site analysis, SPAD localization imaging PLoS pathogens High 39823525
2008 CPSF6 is fused to FGFR1 in the t(8;12)(p11;q15) rearrangement in an 8p11 myeloproliferative syndrome patient; the predicted CPSF6-FGFR1 fusion encodes the N-terminal domain of CPSF6 linked to the entire tyrosine kinase domain and C-terminal sequences of FGFR1. CPSF6 thus acts as a dimerization/oligomerization partner that constitutively activates FGFR1 kinase. Cytogenetics, genomic breakpoint PCR, RT-PCR confirming in-frame fusion Genes, chromosomes & cancer Medium 18205209
2007 CPSF6 and CPSF5 (CFIm subunits) are highly enriched in mouse male germ cells and both subunits are expressed from shorter spermatogenic mRNAs generated by alternative polyadenylation using proximal poly(A) signals; CFIm binding sites were identified near the 3' ends of numerous male germ cell transcripts utilizing noncanonical poly(A) signals, suggesting CPSF6-containing CFIm complexes direct APA at noncanonical signals during spermatogenesis. Northern blotting, cDNA sequencing, RT-PCR, CFIm binding site analysis, Western blot during spermatogenesis Biology of reproduction Medium 18032416
2019 NP1 protein of minute virus of canines (MVC) physically interacts with CPSF6 in transfected cells, and CPSF6 participates with NP1 to modulate suppression of proximal polyadenylation and splicing enhancement at the MVC capsid gene, demonstrating CPSF6 can be co-opted by viral non-retroviral proteins to modulate alternative RNA processing. Co-immunoprecipitation, functional RNA processing assays in transfected cells Journal of virology Medium 30355695
2017 CPSF6 interacts with components of the A-to-I RNA editing machinery and paraspeckles, including ADAR1, and is required for their physical integrity; prolactin suppresses CPSF6 and RNA editing activity, placing CPSF6 in a paraspeckle-regulatory pathway. Co-immunoprecipitation, paraspeckle integrity assays (CPSF6 depletion), prolactin treatment EBioMedicine Medium 28673861
2023 CPSF6 regulates temperature compensation of the mammalian circadian clock; CPSF6 knockdown significantly alters circadian temperature compensation in U-2 OS cells. Global 3' UTR length changes and temperature-dependent gene expression changes in CPSF6 KD cells identify candidate genes including EIF2S1 as underlying circadian temperature compensation. CPSF6 knockdown, 3'-end RNA-seq, mass spectrometry proteomics, circadian period analysis PLoS biology Medium 37379316
2021 CPSF6 knockdown in HCC cells induces widespread 3'UTR lengthening; specifically, CPSF6 drives proximal poly(A) site usage at NQO1, producing a short 3'UTR NQO1 isoform that is more stable and mediates CPSF6-dependent metabolic alterations and tumorigenic activity, establishing a molecular mechanism linking CPSF6-regulated APA to oncogenic phenotype. CPSF6 knockdown, APA profiling (3T-seq), NQO1 isoform functional assays, metabolic assays Journal of experimental & clinical cancer research Medium 33648552
2023 CPSF6 mediates 3'UTR shortening of XBP1 by promoting proximal PAS usage; BRCA1-disrupted R-loop accumulation at the CPSF6 5' end causes CPSF6 elevation, and nuclear LINC00221 facilitates CPSF6-induced proximal PAS choice at pre-XBP1, producing a more stable XBP1-S isoform that contributes to cisplatin resistance in lung adenocarcinoma. CPSF6 manipulation, poly(A) site sequencing, R-loop analysis, luciferase reporter, cisplatin resistance assays Drug resistance updates Medium 36821972
2024 Downregulation of CPSF6 upon viral infection (reduced protein abundance) promotes proximal poly(A) site usage of immune-related genes in macrophages and fibroblasts, shortening their 3' UTRs, which improves mRNA stability and translation efficiency to enhance type I IFN antiviral signaling. CPSF6 knockdown/overexpression, APA sequencing, mRNA stability assays, IFN signaling measurement PLoS pathogens Medium 38416782
2022 FXR1 forms a complex with CFIm25 and CFIm68 (CPSF6) acting as a platform for sequence-specific poly(A) site recognition; this FXR1-CFIm complex affects 3' processing of TRAF1 mRNA, leading to nuclear mRNA stabilization and enhanced cell proliferation in urothelial carcinoma. Co-immunoprecipitation of FXR1-CPSF6/CFIm25 complex, APA analysis, mRNA stability assays Cell death & disease Medium 35194031
2025 CPSF6 KO in primary CD4+ T cells leads to global 3' UTR shortening via APA, downregulation of innate immune genes and restriction factors (including TRIM5α), and upregulation of HIV-1 co-receptors, increasing permissivity to HIV-1 infection. HIV-1 recruitment of CPSF6 to incoming cores is sufficient to perturb CPSF6 function and cause similar APA-driven transcriptional reprogramming. CPSF6 KO in primary CD4+ T cells, APA sequencing, transcriptome analysis, HIV-1 infectivity assays, co-receptor expression measurement PLoS pathogens High 41385587
2024 The CPSF6 FG domain is essential for both HIV-induced nuclear puncta formation and binding to the viral core, which serves as the scaffold for CPSF6 condensates; low-complexity regions and mixed-charge domains modulate CPSF6 binding to capsid but do not contribute to puncta formation. SRRM2's intrinsically disordered region is required for enlarging nuclear speckles in the presence of HIV capsid, and puncta form individually then fuse with nuclear speckles. CPSF6 domain deletion mutants, live imaging, SRRM2 depletion, viral replication assays eLife High 41493399

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 CPSF6 defines a conserved capsid interface that modulates HIV-1 replication. PLoS pathogens 238 22956906
2014 Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. Proceedings of the National Academy of Sciences of the United States of America 232 25518861
2016 A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. Proceedings of the National Academy of Sciences of the United States of America 210 26858452
2017 Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. Molecular cell 179 29276085
2018 Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration. Cell host & microbe 176 30173955
2019 HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex. eLife 164 30672737
2015 Direct Visualization of HIV-1 Replication Intermediates Shows that Capsid and CPSF6 Modulate HIV-1 Intra-nuclear Invasion and Integration. Cell reports 144 26586435
2013 TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm. Retrovirology 122 23414560
2013 The ability of TNPO3-depleted cells to inhibit HIV-1 infection requires CPSF6. Retrovirology 81 23622145
2016 Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo. Journal of virology 58 27307565
2023 CPSF6-mediated XBP1 3'UTR shortening attenuates cisplatin-induced ER stress and elevates chemo-resistance in lung adenocarcinoma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 57 36821972
2020 CPSF6-Dependent Targeting of Speckle-Associated Domains Distinguishes Primate from Nonprimate Lentiviral Integration. mBio 56 32994325
2021 Cytoplasmic CPSF6 Regulates HIV-1 Capsid Trafficking and Infection in a Cyclophilin A-Dependent Manner. mBio 54 33758083
2021 SRSF3 and SRSF7 modulate 3'UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels. Genome biology 53 33706811
2016 The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes. The Journal of biological chemistry 53 26994143
2021 CPSF6 links alternative polyadenylation to metabolism adaption in hepatocellular carcinoma progression. Journal of experimental & clinical cancer research : CR 51 33648552
2019 Differential role for phosphorylation in alternative polyadenylation function versus nuclear import of SR-like protein CPSF6. Nucleic acids research 48 30916345
2016 Cleavage factor Im (CFIm) as a regulator of alternative polyadenylation. Biochemical Society transactions 48 27528751
2007 Pre-messenger RNA cleavage factor I (CFIm): potential role in alternative polyadenylation during spermatogenesis. Biology of reproduction 48 18032416
2017 CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer. EBioMedicine 45 28673861
2013 A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. Journal of virology 45 23658440
2008 The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. Genes, chromosomes & cancer 44 18205209
2014 In vivo functions of CPSF6 for HIV-1 as revealed by HIV-1 capsid evolution in HLA-B27-positive subjects. PLoS pathogens 43 24415937
2023 CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation. Cell reports 40 37777964
2019 Analysis of CA Content and CPSF6 Dependence of Early HIV-1 Replication Complexes in SupT1-R5 Cells. mBio 39 31690677
2018 Truncated CPSF6 Forms Higher-Order Complexes That Bind and Disrupt HIV-1 Capsid. Journal of virology 39 29643241
2018 A case of acute myeloid leukemia with promyelocytic features characterized by expression of a novel RARG-CPSF6 fusion. Blood advances 30 29891591
2015 Fusion of PDGFRB to MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms. Genes, chromosomes & cancer 29 26355392
2022 CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis. Nucleic acids research 27 35234914
2024 Negative Regulation of CPSF6 Suppresses the Warburg Effect and Angiogenesis Leading to Tumor Progression Via c-Myc Signaling Network: Potential Therapeutic Target for Liver Cancer Therapy. International journal of biological sciences 24 38993554
2023 Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. Scientific reports 23 37414787
2020 MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6. Retrovirology 23 32600399
2024 Downregulation of CPSF6 leads to global mRNA 3' UTR shortening and enhanced antiviral immune responses. PLoS pathogens 22 38416782
2022 FXR1 can bind with the CFIm25/CFIm68 complex and promote the progression of urothelial carcinoma of the bladder by stabilizing TRAF1 mRNA. Cell death & disease 20 35194031
2024 HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration. Nucleic acids research 19 39258548
2021 Suppression of CPSF6 Enhances Apoptosis Through Alternative Polyadenylation-Mediated Shortening of the VHL 3'UTR in Gastric Cancer Cells. Frontiers in genetics 19 34594359
2019 Capsid-CPSF6 interaction: Master regulator of nuclear HIV-1 positioning and integration. Journal of life sciences (Westlake Village, Calif.) 19 31448372
2019 Minute Virus of Canines NP1 Protein Interacts with the Cellular Factor CPSF6 To Regulate Viral Alternative RNA Processing. Journal of virology 16 30355695
2023 HIV-Induced CPSF6 Condensates. Journal of molecular biology 15 37061085
2020 The HIV-1 capsid-binding host factor CPSF6 is post-transcriptionally regulated by the cellular microRNA miR-125b. The Journal of biological chemistry 15 32152226
2020 NUDT21 Suppresses Breast Cancer Tumorigenesis Through Regulating CPSF6 Expression. Cancer management and research 15 32431549
2025 Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration. mBio 14 40013779
2021 Acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration. Therapeutic advances in hematology 14 33473264
2022 Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade. Nucleic acids research 12 35993810
2022 Deregulated expression and subcellular localization of CPSF6, a circRNA-binding protein, promote malignant development of esophageal squamous cell carcinoma. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 10 35355934
2024 HIV-1-induced translocation of CPSF6 to biomolecular condensates. Trends in microbiology 9 38267295
2022 CFIm-mediated alternative polyadenylation safeguards the development of mammalian pre-implantation embryos. Stem cell reports 9 36563685
2021 Ribonucleic acid-binding protein CPSF6 promotes glycolysis and suppresses apoptosis in hepatocellular carcinoma cells by inhibiting the BTG2 expression. Biomedical engineering online 9 34217312
2024 Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration. bioRxiv : the preprint server for biology 8 38645162
2022 The roles of CPSF6 in proliferation, apoptosis and tumorigenicity of lung adenocarcinoma. Aging 8 36446361
2025 CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia. Nature communications 7 39805830
2025 The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection. PLoS pathogens 7 39823525
2024 HIV-1 Capsid Rapidly Induces Long-Lived CPSF6 Puncta in Non-Dividing Cells, but Similar Puncta Already Exist in Uninfected T-Cells. Viruses 7 38793552
2025 m6A-mediated regulation of CPSF6 by METTL3 promotes oxaliplatin resistance in colorectal cancer through enhanced glycolysis. Cellular signalling 5 40010558
2025 E3 ligase SYVN1-mediated polyubiquitination of CPSF6 promotes alternative polyadenylation and antivirus effects of macrophages. Cell reports 4 39951376
2023 Alternative polyadenylation factor CPSF6 regulates temperature compensation of the mammalian circadian clock. PLoS biology 4 37379316
2023 A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway. eLife 4 37665675
2025 CPSF6 promotes HIV-1 preintegration complex function. Journal of virology 3 40202316
2025 IGF2BP2 binding to CPSF6 facilitates m6A-mediated alternative polyadenylation of PUM2 and promotes malignant progression in ovarian cancer. Clinical and translational medicine 3 40629911
2023 RNA-binding protein CPSF6 regulates IBSP to affect pyroptosis in gastric cancer. World journal of gastrointestinal oncology 3 37746647
2022 Case report: A rare case of acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia. Frontiers in oncology 3 36185228
2019 Effect of CFIm68 knockdown on RNA polymerase II transcription. BMC research notes 3 31477156
2016 Evidence that a threshold of serine/arginine-rich (SR) proteins recruits CFIm to promote rous sarcoma virus mRNA 3' end formation. Virology 3 27596537
2026 Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with nuclear speckles. eLife 2 41493399
2024 Detection of CPSF6 in Biomolecular Condensates as a Reporter of HIV-1 Nuclear Import. Methods in molecular biology (Clifton, N.J.) 2 38743225
2024 The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection. bioRxiv : the preprint server for biology 2 38979149
2020 The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1. AIDS research and human retroviruses 2 31941344
2025 CPSF6 loss mediates LDHA 3'UTR shortening to promote fibroblast glycolysis and pulmonary fibrosis. Cellular signalling 1 41076169
2025 Alternative polyadenylation upon CPSF6 knock-out enhances HIV-1 infection in primary T cells. PLoS pathogens 1 41385587
2024 CircSugp1 interacts with CPSF6 to modulate intestinal mucosa repair by regulating alternative polyadenylation-mediated shortening of the Wdr89 3'UTR. International immunopharmacology 1 39662264
2024 Disruption of CPSF6 enhances cellular permissivity to HIV-1 infection through alternative polyadenylation. Research square 1 39678349
2022 [The nuclear translocation of circRNA CPSF6 promotes apoptosis of trophoblast cells induced by homocysteine]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 35356883
2020 Expression of zebrafish cpsf6 in embryogenesis and role of protein domains on subcellular localization. Gene expression patterns : GEP 1 32330562
2026 CPSF6-mediated alternative polyadenylation of RUNX1 to regulate silica-induced pulmonary fibrosis progression. Respiratory research 0 41540455
2026 A stress-dependent postembryonic role for the core CPA factor CFIM-1 in germline integrity. Genetics 0 41606827
2026 Apoptosis and Metabolic Reprogramming by RHART in Hepatocellular Carcinoma Through the CPSF6/MCT4/c-Myc Signaling In Vitro and In Vivo. Phytotherapy research : PTR 0 41708579
2026 Block-and-Lock Approaches for HIV Cure: Mechanistic Insights, Challenges, and Emerging Role of CPSF6. International journal of molecular sciences 0 42074139
2025 Inhibiting circ_0000673 blocks the progression of colorectal cancer through downregulating CPSF6 via targeting miR-548b-3p. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 0 39225594
2025 Loss of CFIm activates YAP/TAZ and connects mRNA cleavage and polyadenylation inhibition to BRCAness. bioRxiv : the preprint server for biology 0 41278918
2024 Retraction note to: RNA-binding protein CPSF6 regulates IBSP to affect pyroptosis in gastric cancer. World journal of gastrointestinal oncology 0 38994163

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