Affinage

CPSF6

Cleavage and polyadenylation specificity factor subunit 6 · UniProt Q16630

Length
551 aa
Mass
59.2 kDa
Annotated
2026-04-28
79 papers in source corpus 34 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CPSF6 is a multifunctional RNA-processing factor and HIV-1 host cofactor that couples mRNA 3'-end formation with viral nuclear trafficking and integration targeting. As a subunit of the cleavage factor I (CFIm) complex with CPSF5/NUDT21, CPSF6 binds UGUA-containing enhancer elements to activate distal poly(A) site usage, with its RS-like domain engaging Fip1 to promote 3'-end processing; phosphorylation by CLK2 disrupts CPSF6 liquid-liquid phase separation and shifts polyadenylation toward proximal sites, causing 3' UTR shortening of cell-cycle and immune-related transcripts (PMID:29276085, PMID:37777964, PMID:38416782). CPSF6's FG-motif-containing domain binds the NTD–CTD interface of the assembled HIV-1 capsid hexamer with high affinity, and sequential handoff from cytoplasmic CypA to nuclear CPSF6 enables viral cores to traverse nuclear pores, bypass peripheral heterochromatin, and reach speckle-associated domains where CPSF6 forms biomolecular condensates with CPSF5 that directly stimulate preintegration complex integration activity (PMID:25518861, PMID:30173955, PMID:37414787, PMID:40202316, PMID:40013779). Upon viral infection, SYVN1-mediated K48-linked polyubiquitination targets CPSF6 for proteasomal degradation, triggering transcriptome-wide APA and enhancing type I interferon signaling, while HIV-1 co-option of CPSF6 itself perturbs host APA to downregulate restriction factors and increase viral permissivity (PMID:39951376, PMID:41385587).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 Medium

    Establishing CPSF6 as a CFIm subunit that participates in noncanonical poly(A) site selection resolved how AAUAAA-independent polyadenylation could be directed during tissue-specific gene expression.

    Evidence cDNA sequencing and Northern blotting identifying CFIm binding sites in mouse germ cell transcripts

    PMID:18032416

    Open questions at the time
    • No direct functional disruption of CPSF6 was performed
    • Binding site identification was correlative without APA rescue
  2. 2012 High

    Structural identification of the CPSF6-binding pocket on HIV-1 capsid NTD established the molecular basis for CPSF6 as a direct capsid cofactor and linked it to nuclear entry pathway dependence.

    Evidence X-ray crystallography of CA NTD–CPSF6 peptide complex with mutagenesis and infection assays

    PMID:22956906

    Open questions at the time
    • Binding was shown to isolated NTD, not assembled hexamer
    • Affinity for lattice context unknown
  3. 2013 High

    Demonstrating that TNPO3 maintains CPSF6 nuclear localization resolved the paradox of why TNPO3 depletion blocks HIV-1: cytoplasmic CPSF6 hyper-stabilizes incoming capsids, and truncated CPSF6-375 accelerates uncoating, establishing that CPSF6's subcellular compartmentalization dictates its pro- versus anti-viral activity.

    Evidence TNPO3 knockdown with CPSF6 mislocalization constructs, fate-of-capsid assays, and cDNA synthesis measurements

    PMID:23414560 PMID:23622145 PMID:23658440

    Open questions at the time
    • Mechanism by which cytoplasmic CPSF6 destabilizes capsid was not structurally resolved
    • Stoichiometry of CPSF6 binding required for restriction unknown
  4. 2014 High

    Showing that CPSF6 binds the NTD–CTD inter-domain pocket of assembled CA hexamers with ≥10-fold preference over monomeric CA established the capsid lattice as the physiological binding target.

    Evidence Quantitative binding assays comparing assembled versus unassembled CA, X-ray crystallography of PF74–hexamer complex revealing shared pocket

    PMID:25518861

    Open questions at the time
    • Full-length CPSF6–hexamer structure not obtained
    • Kinetic parameters of binding not determined
  5. 2016 High

    Genetic epistasis experiments revealed that CPSF6 dominates over LEDGF/p75 in directing HIV-1 integration to transcriptionally active euchromatin, and that this function depends on capsid binding but not on CPSF6's incorporation into the CFIm complex.

    Evidence CPSF6 KO/KD combined with LEDGF depletion, integration site sequencing, and CFIm-incorporation mutant analysis

    PMID:26858452 PMID:26994143

    Open questions at the time
    • How CPSF6 mechanistically selects euchromatic targets remained unclear
    • Whether CPSF6 acts before or after uncoating was unresolved
  6. 2017 High

    Defining CPSF6's RS domain as the interface for Fip1 binding and showing that CFIm acts as an enhancer-dependent activator of 3'-end processing established the molecular mechanism by which CPSF6 regulates global alternative polyadenylation.

    Evidence iCLIP, 3'-seq, RS domain mutagenesis, phosphorylation mimetic mutants

    PMID:29276085

    Open questions at the time
    • Structural basis of RS–Fip1 interaction not determined
    • In vivo phosphorylation sites controlling this interaction not mapped
  7. 2018 High

    Imaging HIV-1 replication intermediates demonstrated that CPSF6–capsid interaction licenses deep nuclear penetration past peripheral heterochromatin, while higher-order CPSF6-358 oligomers physically disrupt capsid tubes, resolving the dual role of CPSF6 stoichiometry.

    Evidence Fluorescence microscopy of HIV-1 in CPSF6 KO cells showing nuclear periphery arrest; in vitro reconstitution and EM of CPSF6-358 disrupting CA tubes

    PMID:29643241 PMID:30173955

    Open questions at the time
    • Whether intact capsid transits the nuclear pore was debated
    • Threshold stoichiometry for capsid disruption versus facilitation undefined
  8. 2019 High

    Crystal structure of the CPSF6 RSLD–TNPO3 complex defined the nuclear import mechanism and showed that hyperphosphorylation blocks TNPO3 binding, linking CPSF6 phosphoregulation to both nuclear localization and APA control.

    Evidence X-ray crystallography of RSLD–TNPO3, phosphomimetic mutagenesis, nuclear import assays, APA analysis

    PMID:30916345

    Open questions at the time
    • Identity of the kinase(s) responsible for physiological RSLD phosphorylation was not determined at this stage
    • Super-resolution imaging of CPSF6 in nuclear pores showed that CPSF6-binding-deficient virus arrests inside the pore but mechanism of pore release was unknown
  9. 2020 High

    Large-scale integration site mapping across primate and non-primate lentiviruses demonstrated that CPSF6 interaction is an evolved primate lentiviral adaptation that specifically targets integration to nuclear speckle-associated domains (SPADs).

    Evidence Millions of integration sites mapped with CPSF6 KO/KD; non-primate capsids fail to bind CPSF6 or target SPADs

    PMID:32994325

    Open questions at the time
    • Structural determinants on non-primate capsids that prevent CPSF6 binding not identified
    • Functional consequence of SPAD-targeted integration for viral gene expression not tested
  10. 2021 High

    Demonstrating that CypA shields cytoplasmic HIV-1 capsid from premature CPSF6 engagement established the sequential handoff model: CypA binding in the cytoplasm prevents higher-order CPSF6 complex formation until capsid reaches the nuclear compartment.

    Evidence Live-cell imaging, in vitro capsid disruption assays, CypA disruption experiments

    PMID:33758083

    Open questions at the time
    • Whether CypA and CPSF6 binding sites overlap or allosterically communicate was not structurally resolved
    • Timing of CypA dissociation during nuclear import not determined
  11. 2023 High

    CPSF6 undergoes liquid-liquid phase separation controlled by CLK2-mediated RS domain phosphorylation; disrupted LLPS shifts polyadenylation to proximal sites, linking phase separation biophysics to cancer-relevant APA and cell proliferation. Concurrently, HIV-1 CA triggers CPSF6/CPSF5 biomolecular condensates at nuclear speckles that form independently of reverse transcription or integration.

    Evidence In vitro LLPS reconstitution with CLK2 phosphorylation, APA-seq; fluorescence microscopy with hexanediol disruption and CA-binding-deficient mutants

    PMID:37414787 PMID:37777964

    Open questions at the time
    • Whether CPSF6 condensate formation at speckles directly enhances integration versus simply colocalizes was unclear
    • Material properties (viscosity, dynamics) of CPSF6 condensates not characterized
  12. 2024 High

    Dissection of the CPSF6 mixed-charge domain (MCD) and FG domain revealed their distinct roles: the FG peptide drives HIV-induced puncta formation and capsid binding, while the MCD enables LLPS-dependent higher-order binding required for nuclear interior penetration past the nuclear rim.

    Evidence Domain deletion/swap mutagenesis, in vitro LLPS and capsid binding assays, live imaging, integration site sequencing, SRRM2 depletion

    PMID:39258548 PMID:41493399

    Open questions at the time
    • Structural basis of MCD-mediated phase separation not determined
    • How FG-domain puncta fuse with nuclear speckles mechanistically unresolved
  13. 2025 High

    Multiple convergent studies established that CPSF6 directly stimulates PIC integration activity, that its specific NLS governs post-import intranuclear positioning beyond simple nuclear entry, and that SYVN1-mediated proteasomal degradation of CPSF6 triggers APA-driven innate immune enhancement—while HIV-1 co-opts CPSF6 to suppress restriction factors via the same APA mechanism.

    Evidence In vitro PIC reconstitution with purified CPSF6; NLS chimera constructs with integration site analysis; SYVN1 ubiquitination assays with K48-linkage identification; CPSF6 KO in primary CD4+ T cells with APA-seq and restriction factor analysis

    PMID:39823525 PMID:39951376 PMID:40202316 PMID:41385587

    Open questions at the time
    • How CPSF6 biochemically enhances integrase catalytic activity remains unknown
    • Whether CPSF6 degradation during HIV infection also enhances innate immunity or is fully co-opted is unresolved
    • Structural basis of how the native CPSF6 NLS directs intranuclear SPAD trafficking not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of full-length CPSF6 bound to the assembled capsid lattice, the biochemical mechanism by which CPSF6 stimulates integrase activity within the PIC, and how the balance between CPSF6 phase separation and degradation is regulated to coordinate APA output in different cellular contexts.
  • No cryo-EM or crystal structure of full-length CPSF6 on intact capsid lattice
  • Integrase activation mechanism by CPSF6 completely uncharacterized
  • Quantitative model linking CPSF6 condensate dynamics to APA site selection absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 6 GO:0005654 nucleoplasm 4 GO:0005829 cytosol 3
Pathway
R-HSA-1643685 Disease 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-8953854 Metabolism of RNA 5 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 1
Partners
ADAR1CPSF7FIP1L1NUDT21SRRM2SYVN1TNPO3
Complex memberships
CFIm (cleavage factor Im)HIV-1 capsid-CPSF6 complex

Evidence

Reading pass · 33 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 (NTD) of HIV-1 capsid (CA), identified by X-ray crystallography. This interface is conserved across lentiviruses and is accessible in the context of a hexameric CA lattice. Mutations at this interface prevent CPSF6 binding and relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. X-ray crystallography, mutagenesis, binding assays, viral infection assays PLoS pathogens High 22956906
2014 CPSF6 binds to the NTD-CTD interface of the assembled HIV-1 CA hexamer (the same pocket as PF74 and NUP153) with at least 10-fold higher affinity compared with non-assembled CA or isolated CA domains, indicating that the principal binding target of CPSF6 is the assembled capsid lattice. Biochemical binding assays, X-ray crystallography of PF74-CA hexamer complex Proceedings of the National Academy of Sciences of the United States of America High 25518861
2013 TNPO3 promotes HIV-1 infectivity indirectly by keeping CPSF6 in the nucleus; when TNPO3 is depleted, CPSF6 accumulates in the cytoplasm, binds the incoming capsid, and causes abnormal stabilization (excessive stability) of the HIV-1 CA core, blocking infection. Targeting CPSF6 to the nucleus with a heterologous NLS rescued HIV-1 from TNPO3-knockdown inhibition. TNPO3 knockdown, CPSF6 mislocalization constructs (NLS deletion, NES fusion, heterologous NLS), fate-of-capsid assays, qPCR for 2-LTR circles Retrovirology High 23414560 23622145
2016 CPSF6 directs HIV-1 integration to transcriptionally active euchromatin (spliced genes, chromatin enriched in activating histone marks) via its capsid-binding activity. CPSF6 knockout changed integration site distribution, and a capsid-binding mutant of CPSF6 failed to rescue this phenotype. CPSF6 plays a more dominant role than LEDGF/p75 in directing integration to euchromatin. CPSF6 knockout and knockdown (alone and combined with LEDGF/p75 depletion), integration site sequencing, CPSF6 complementation with wild-type or 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 together with CPSF5 and CPSF7. HIV-1 capsid recruits the CFIm complex in a CPSF6-dependent manner. However, CPSF6 incorporation into CFIm is not required for CPSF6 to direct HIV-1 integration into genes; CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin. Biochemical fractionation, co-immunoprecipitation, CFIm-incorporation mutant analysis, integration site sequencing The Journal of biological chemistry High 26994143
2017 CFIm complex, composed of CPSF6 (CFIm68) and CPSF5 (CFIm25), functions as an enhancer-dependent activator of mRNA 3'-end processing and regulates global alternative polyadenylation (APA) by specifically binding and activating enhancer-containing poly(A) sites. The activator function of CPSF6 is mediated by its RS domain, which binds specifically to an RS-like region in the CPSF subunit Fip1; this interaction is inhibited by CFIm68/59 hyper-phosphorylation. iCLIP, 3'-seq, biochemical interaction assays, RS domain mutagenesis, phosphorylation mimetic mutants Molecular cell High 29276085
2018 Capsid-CPSF6 interaction licenses HIV-1 nuclear trafficking: CPSF6-capsid interactions allow the virus to bypass peripheral heterochromatin and penetrate the nuclear interior. Loss of this interaction dramatically relocates HIV-1 preintegration complexes to the nuclear periphery and redirects integration into transcriptionally repressed lamina-associated heterochromatin, whereas loss of LEDGF/p75 does not significantly affect intranuclear HIV-1 localization. Fluorescence microscopy imaging of HIV-1 replication intermediates, CPSF6 knockout, integration site mapping, LEDGF/p75 depletion comparison Cell host & microbe High 30173955
2018 Truncated CPSF6-358 forms higher-order oligomeric complexes that bind directly to assembled wild-type HIV-1 CA tubes in vitro and physically disrupt the tubular assemblies. In cells, CPSF6-358 forms cytoplasmic puncta upon WT HIV-1 infection and leads to capsid permeabilization. These events require intact CA binding sites and are blocked by a small-molecule capsid inhibitor. In vitro binding of purified CPSF6-358 to assembled CA tubes, transmission electron microscopy, live-cell imaging, fixed-cell confocal microscopy Journal of virology High 29643241
2019 CPSF6 is strongly recruited to nuclear HIV-1 replication complexes (but not 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. Two-color STED microscopy revealed that CPSF6-binding-deficient complexes are retained inside the nuclear pore. HIV-1 nuclear entry in macrophages is proposed to be mediated by consecutive binding of Nup153 and CPSF6 to the hexameric CA lattice. Quantitative fluorescence microscopy, CPSF6 depletion, stimulated emission 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 causes unnaturally extended 3' UTRs. Crystal structure of RSLD-TNPO3 complex, mutagenesis, nuclear import assays, phosphomimetic mutants, APA analysis Nucleic acids research High 30916345
2013 A carboxy-terminally truncated CPSF6 (hCPSF6-375, lacking exon 6) inhibits HIV-1 cDNA synthesis and aberrantly accelerates viral capsid disassembly in target cells. Mutational analysis showed that residues encoded by exon 6, not the C-terminal 54 residues, are responsible for the impaired viral cDNA synthesis phenotype. cDNA expression cloning with ganciclovir-mediated lethal selection, fate-of-capsid assays, mutagenesis, HIV-1 infection assays Journal of virology Medium 23658440
2015 CA enters the nucleus and associates with viral DNA (vDNA) in both transformed and primary cells. CA's interaction with CPSF6 enhances nuclear entry and potentiates HIV-1's depth of nuclear invasion, potentially aiding integration into gene-dense regions. ViewHIV imaging approach combining capsid protein and viral DNA detection by confocal microscopy in single cells, CPSF6 manipulation Cell reports Medium 26586435
2020 Primate lentiviral capsid proteins (including HIV-1) evolved to interact with CPSF6 to direct preintegration complexes to nuclear speckle-associated domains (SPADs) for integration. Non-primate lentiviral capsids fail to interact appreciably with CPSF6, which is reflected in their failure to target SPADs. CPSF6 depletion specifically counteracts SPAD integration targeting by primate lentiviruses. Integration site mapping of millions of sites, CPSF6 depletion/knockout, co-immunoprecipitation of nonprimate capsids with CPSF6 mBio High 32994325
2021 HIV-1 infection induces higher-order CPSF6 formation; capsid-CPSF6 complexes co-traffic on microtubules. Higher-order CPSF6 complexes bind and 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, in vitro capsid assembly disruption assays, CypA disruption experiments, co-trafficking microscopy mBio High 33758083
2021 CPSF6 is required for CPSF6-induced APA regulation in hepatocellular carcinoma via promoting preferential usage of the proximal poly(A) site in the 3'UTR of NQO1, leading to a short NQO1 isoform that mediates metabolic alterations in HCC cells. Deep sequencing-based 3T-seq APA profiling, CPSF6 knockdown/overexpression, cell viability and metabolic assays, in vivo xenograft Journal of experimental & clinical cancer research : CR Medium 33648552
2023 HIV-1 entry into the nucleus triggers translocation of CPSF6 from paraspeckles into nuclear speckles, forming CPSF6/CPSF5 biomolecular condensates. Neither viral integration nor reverse transcription is required for condensate formation; viral cores without genome are sufficient. These condensates depend on the physical presence of viral CA in the nucleus, are sensitive to osmotic stress and 1,6-hexanediol, and are important for productive HIV-1 infection. LEDGF/p75 relocates to surround these condensates. Fluorescence microscopy, osmotic stress/hexanediol disruption, HIV-1 mutant infection (N74D, A77V), CPSF6/CPSF5 co-localization in T cells and macrophages Scientific reports High 37414787
2023 CPSF6 undergoes liquid-liquid phase separation (LLPS) in vitro and in cells. CLK2 kinase (upregulated in cancer) phosphorylates the CPSF6 arginine/serine-like domain, disrupting CPSF6 LLPS. Reduced CPSF6 LLPS leads to preferential proximal poly(A) site usage and 3' UTR shortening of cell-cycle-related genes, promoting cancer cell proliferation. In vitro LLPS assays, CLK2 kinase activity assays, phosphorylation mutagenesis, APA sequencing, cell proliferation assays Cell reports High 37777964
2024 The mixed-charge domain (MCD) of CPSF6 is required for LLPS-dependent higher-order binding and co-aggregation with HIV-1 capsids in vitro and in cells. Loss of MCD causes HIV-1 to arrest at the nuclear rim without penetrating the nuclear interior. Heterologous MCDs can substitute for CPSF6 MCD function during HIV-1 infection, but Arg-Ser domains from SR proteins cannot. Nuclear speckle depletion reduces CPSF6 puncta but does not significantly impair integration into speckle-proximal chromatin. In vitro LLPS assays, capsid binding affinity measurements, live imaging of HIV-1 infection, integration site sequencing, MCD deletion and substitution mutagenesis Nucleic acids research High 39258548
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. Addition of purified recombinant CPSF6 restored PIC integration activity in CPSF6-binding-mutant cells, demonstrating a direct stimulatory role. Loss of CA-CPSF6 interaction in infected cells reduces viral DNA integration and redirects it away from gene-dense chromatin. PIC extraction and in vitro integration assay, recombinant CPSF6 complementation, integration site sequencing, reverse transcription and nuclear entry controls Journal of virology High 40202316
2025 Sequential, spatiotemporal binding of CypA and CPSF6 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; disruption of CypA binding to this mutant restores nuclear entry, integration, and infection in a CPSF6-dependent manner. Nuclear re-localization of CypA fails to restore mutant HIV-1 infection, indicating cytoplasmic CypA-to-nuclear CPSF6 handoff is required. Capsid mutant infection assays, CypA relocalization constructs, CPSF6-dependent rescue assays, integration site mapping mBio High 40013779
2025 SYVN1 E3 ligase (whose nuclear import is triggered by MAVS via NUP153 upon VSV infection) catalyzes K48-linked polyubiquitination of CPSF6, leading to proteasomal degradation of CPSF6 and consequent transcriptome-wide APA in macrophages to enhance antiviral effects. Co-immunoprecipitation, ubiquitination assays identifying K48 linkage, proteasome inhibitor experiments, siRNA knockdown, APA sequencing Cell reports High 39951376
2025 The CPSF6-RARG fusion oncoprotein interacts with histone deacetylase 3 (HDAC3) to suppress expression of myeloid differentiation genes including PU.1, thereby impairing myeloid maturation and driving leukemia. Disrupting the CPSF6-RARG/HDAC3 interaction restores PU.1 expression and myeloid differentiation. HDAC inhibitors suppress CPSF6-RARG-driven leukemia in vitro and in vivo. Co-immunoprecipitation of CPSF6-RARG with HDAC3, gene expression analysis, HDAC inhibitor treatment, mouse leukemia model Nature communications High 39805830
2025 The nuclear localization signal (NLS) of CPSF6 governs post-nuclear import steps of HIV-1 infection: some heterologous NLSs can drive CPSF6-358 into the nucleus but fail to support trafficking of HIV-1 to speckle-associated domains (SPADs) and efficient integration, even though HIV-1 still enters the nucleus. Thus, the specific NLS of CPSF6 facilitates intranuclear HIV-1 positioning beyond nuclear import itself. CPSF6 truncation with heterologous NLS appending, HIV-1 infection assays, imaging of nuclear HIV-1 localization, integration site analysis PLoS pathogens High 39823525
2007 CPSF6 (and CPSF5/NUDT21) are components of the pre-mRNA cleavage factor I (CFIm) complex that can direct AAUAAA-independent polyadenylation site selection. In mouse male germ cells, CFIm binding sites near the 3' ends of numerous transcripts suggest CFIm/CPSF6 participates in alternative polyadenylation directed by noncanonical poly(A) signals during spermatogenesis. cDNA sequencing, Northern blotting, quantitative RT-PCR, developmental Western blot analysis, identification of CFIm binding sites Biology of reproduction Medium 18032416
2008 CPSF6 is fused to FGFR1 in t(8;12)(p11;q15) translocation creating an in-frame CPSF6-FGFR1 oncogenic fusion retaining the N-terminal domain of CPSF6 and the entire FGFR1 tyrosine kinase domain. This is a recurrent theme as SFPQ, another pre-mRNA processing protein, also fuses with ABL and with FGFR1 partners. Genomic breakpoint PCR amplification, RT-PCR confirmation of fusion transcripts Genes, chromosomes & cancer Medium 18205209
2020 miR-125b post-transcriptionally regulates CPSF6 expression by binding to a conserved site in the CPSF6 3'UTR. HIV-1 infection downregulates miR-125b (dependent on reverse transcription but not integration), concurrent with CPSF6 upregulation. Luciferase reporter assays and pulldown experiments confirmed direct miR-125b interaction with CPSF6 3'UTR. Luciferase reporter assay with CPSF6 3'UTR, miR-125b seed sequence mutagenesis, RNA pulldown, miR-125b knockdown/overexpression The Journal of biological chemistry Medium 32152226
2024 CPSF6 downregulation upon viral infection is mediated by SYVN1-mediated proteasomal degradation, resulting in global mRNA 3' UTR shortening through APA and promotion of type I IFN signaling. CPSF6 protein reduction favors usage of proximal poly(A) sites in many immune-related genes in macrophages and fibroblasts. CPSF6 knockdown/knockout, APA sequencing, viral infection experiments, IFN signaling assays PLoS pathogens Medium 38416782
2019 MxB represses NUP358-mediated HIV-1 PIC nuclear import and HIV-1 replication cooperatively with CPSF6. MxB binds NUP358 and blocks NUP358-CA interaction, thereby impeding nuclear import of HIV-1 PIC when CPSF6 is bound to PIC. CPSF6 facilitates nuclear import on its own but becomes an inhibitor when MxB is present. Co-immunoprecipitation, HIV-1 infection assays with MxB overexpression/knockdown and CPSF6 depletion, 2-LTR circle measurement Retrovirology Medium 32600399
2025 CPSF6 knockout in primary CD4+ T cells leads to APA-mediated global 3' UTR shortening, downregulation of innate immune response genes and restriction factors (including TRIM5α), and enhanced HIV-1 co-receptor expression, collectively increasing HIV-1 permissivity. Recruitment of CPSF6 by HIV-1 cores is sufficient to perturb CPSF6 function and trigger similar transcriptional rewiring. CPSF6 knockout in primary T cells, APA sequencing, gene expression analysis, HIV-1 infection assays, IFN response assays PLoS pathogens High 41385587
2023 CPSF6 binds to components of the paraspeckle and A-to-I RNA editing machinery, including ADAR1, and is required for their physical integrity in breast cancer cells. Loss of CPSF6 disrupts paraspeckle architecture. Co-immunoprecipitation of CPSF6 with paraspeckle components and ADAR1, paraspeckle integrity assays upon CPSF6 depletion EBioMedicine Medium 28673861
2020 NUDT21 (CFIm25) directly interacts with CPSF6 (CFIm68) and negatively regulates CPSF6 expression. Knockdown of CPSF6 reversed NUDT21 depletion-induced cancer cell migration and invasion in breast cancer cells. Mass spectrometry, Western blotting, siRNA knockdown, migration/invasion assays Cancer management and research Low 32431549
2023 CPSF6 regulates circadian temperature compensation: CPSF6 knockdown significantly alters free-running period responses to temperature in human U-2 OS cells. 3'-end RNA-seq and proteomics identified candidate downstream targets including EIF2S1 whose temperature-dependent responses are altered upon CPSF6 knockdown. CPSF6 siRNA knockdown, circadian period analysis, 3'-end RNA-seq for APA changes, mass spectrometry proteomics PLoS biology Medium 37379316
2024 The FG domain of CPSF6 is essential for both binding to the HIV-1 viral core and formation of HIV-induced CPSF6 nuclear puncta. The FG peptide (not LCRs or MCDs) drives puncta formation. SRRM2's intrinsically disordered region is required for enlarging nuclear speckles in the presence of HIV capsid. HIV-induced CPSF6 puncta form individually and later fuse with nuclear speckles. Genetic manipulation and depletion of CPSF6 domains, fluorescence microscopy, SRRM2 depletion, domain swap experiments eLife High 41493399

Source papers

Stage 0 corpus · 79 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 237 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 229 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 208 26858452
2017 Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. Molecular cell 176 29276085
2018 Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration. Cell host & microbe 173 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 143 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
2020 CPSF6-Dependent Targeting of Speckle-Associated Domains Distinguishes Primate from Nonprimate Lentiviral Integration. mBio 54 32994325
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 53 36821972
2021 Cytoplasmic CPSF6 Regulates HIV-1 Capsid Trafficking and Infection in a Cyclophilin A-Dependent Manner. mBio 53 33758083
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
2021 SRSF3 and SRSF7 modulate 3'UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels. Genome biology 50 33706811
2007 Pre-messenger RNA cleavage factor I (CFIm): potential role in alternative polyadenylation during spermatogenesis. Biology of reproduction 47 18032416
2019 Differential role for phosphorylation in alternative polyadenylation function versus nuclear import of SR-like protein CPSF6. Nucleic acids research 46 30916345
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
2016 Cleavage factor Im (CFIm) as a regulator of alternative polyadenylation. Biochemical Society transactions 44 27528751
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
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
2023 CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation. Cell reports 38 37777964
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 28 26355392
2022 CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis. Nucleic acids research 25 35234914
2020 MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6. Retrovirology 23 32600399
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 22 38993554
2023 Formation of nuclear CPSF6/CPSF5 biomolecular condensates upon HIV-1 entry into the nucleus is important for productive infection. Scientific reports 22 37414787
2024 Downregulation of CPSF6 leads to global mRNA 3' UTR shortening and enhanced antiviral immune responses. PLoS pathogens 19 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 19 35194031
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
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 17 39258548
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
2021 Acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration. Therapeutic advances in hematology 14 33473264
2025 Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration. mBio 11 40013779
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
2022 Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade. Nucleic acids research 10 35993810
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 HIV-1-induced translocation of CPSF6 to biomolecular condensates. Trends in microbiology 8 38267295
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
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 The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection. PLoS pathogens 6 39823525
2025 m6A-mediated regulation of CPSF6 by METTL3 promotes oxaliplatin resistance in colorectal cancer through enhanced glycolysis. Cellular signalling 4 40010558
2023 A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway. eLife 4 37665675
2025 E3 ligase SYVN1-mediated polyubiquitination of CPSF6 promotes alternative polyadenylation and antivirus effects of macrophages. Cell reports 3 39951376
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
2025 CPSF6 promotes HIV-1 preintegration complex function. Journal of virology 2 40202316
2025 IGF2BP2 binding to CPSF6 facilitates m6A-mediated alternative polyadenylation of PUM2 and promotes malignant progression in ovarian cancer. Clinical and translational medicine 2 40629911
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
2023 Alternative polyadenylation factor CPSF6 regulates temperature compensation of the mammalian circadian clock. PLoS biology 2 37379316
2020 The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1. AIDS research and human retroviruses 2 31941344
2016 Evidence that a threshold of serine/arginine-rich (SR) proteins recruits CFIm to promote rous sarcoma virus mRNA 3' end formation. Virology 2 27596537
2025 CPSF6 loss mediates LDHA 3'UTR shortening to promote fibroblast glycolysis and pulmonary fibrosis. Cellular signalling 1 41076169
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 Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with nuclear speckles. eLife 0 41493399
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
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
2025 Alternative polyadenylation upon CPSF6 knock-out enhances HIV-1 infection in primary T cells. PLoS pathogens 0 41385587
2024 Retraction note to: RNA-binding protein CPSF6 regulates IBSP to affect pyroptosis in gastric cancer. World journal of gastrointestinal oncology 0 38994163