Affinage

PAIP2

Polyadenylate-binding protein-interacting protein 2 · UniProt Q9BPZ3

Length
127 aa
Mass
15.0 kDa
Annotated
2026-06-10
16 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAIP2 (Paip2A) is a translational repressor that controls cytoplasmic translation by antagonizing poly(A)-binding protein (PABP/PABPC1) (PMID:11172725). It binds PABP at two sites via two contact regions on PABP and decreases PABP affinity for polyadenylate RNA, disrupting poly(A) RNP structure and selectively inhibiting translation of poly(A)-containing mRNAs while sparing cap- and eIF4G-independent IRES translation (PMID:11172725, PMID:11438674). PAIP2 engages the RRM2–RRM3 region of PABPC1 with ~1 nM affinity and displaces it from poly(A) through a sequential mechanism in which RRM2-anchored PAIP2 dislodges RRM3 from the poly(A) tail (PMID:35307347), reversing the bent, poly(A)-induced PABP conformation into an extended state (PMID:24293655). PAIP2 represses translation by a second, independent route: competing with eIF4G for PABP binding even when PABP is tethered to mRNA (PMID:16772376), and it also blocks free PABP from stimulating eRF3a-dependent translation termination (PMID:30992367). PAIP2 abundance is set by a homeostatic feedback loop in which the E3 ubiquitin ligase EDD ubiquitinates PAIP2 for proteasomal degradation upon PABP depletion, coupling PAIP2 stability to PABP levels (PMID:16601676). Genetically, Paip2a/Paip2b loss in mice causes male infertility through aberrant PABP overexpression that impairs eIF4E–cap interaction and blocks the translational activation required for late spermiogenesis (PMID:20739757). Beyond its cytoplasmic role, a nuclear pool of the Drosophila ortholog associates co-transcriptionally with chromatin at active promoters and cooperates with capping and TREX-2 factors in mRNA processing (PMID:31001806, PMID:29995569, PMID:39707855).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established that PAIP2 is a dedicated PABP-interacting translational repressor that works by lowering PABP affinity for the poly(A) tail, defining the gene's core biological role.

    Evidence In vitro translation assays, in vivo transfection, PABP–poly(A) binding and competition assays

    PMID:11172725

    Open questions at the time
    • Did not define the structural basis or affinity of the PAIP2–PABP interaction
    • Did not address how PAIP2 levels are regulated in cells
  2. 2001 High

    Quantified the bivalent PAIP2–PABP architecture, showing two binding sites on each partner with 2:1 stoichiometry and identifying the central PABP-RRM-binding fragment as the active repressive module.

    Evidence Biacore surface plasmon resonance, far-Western, deletion mapping

    PMID:11438674

    Open questions at the time
    • Did not resolve the atomic-level RRM contacts
    • Did not establish which interaction operates in vivo
  3. 2006 High

    Revealed that PAIP2 abundance is homeostatically coupled to PABP via EDD-mediated ubiquitination and proteasomal degradation, explaining how repressor and target levels are balanced.

    Evidence RNAi knockdown of PABP and EDD, reciprocal Co-IP, ubiquitination and protein-stability assays

    PMID:16601676

    Open questions at the time
    • Did not identify the ubiquitinated residues on PAIP2
    • Did not establish how PABP binding shields PAIP2 from EDD
  4. 2006 High

    Demonstrated a second, poly(A)-displacement-independent repression mechanism whereby PAIP2 competes with eIF4G for PABP, broadening the model beyond simple poly(A) release.

    Evidence In vitro translation with tethered PABP, competition binding

    PMID:16772376

    Open questions at the time
    • Did not quantify the relative contribution of each mechanism in vivo
  5. 2006 Medium

    Showed the paralog Paip2B represses translation by the same poly(A)-displacement mechanism but is more stable than the more heavily ubiquitinated Paip2A, distinguishing the two family members.

    Evidence In vitro/in vivo translation assays, ubiquitination assay, proteasome inhibition

    PMID:16804161

    Open questions at the time
    • Single-lab paralog comparison
    • Did not establish distinct physiological roles for Paip2A vs Paip2B
  6. 2010 High

    Provided in vivo genetic proof that PAIP2-mediated PABP homeostasis is essential, as its loss causes male infertility through PABP overexpression that impairs eIF4E–cap binding during spermiogenesis.

    Evidence Single and double knockout mice, polysome profiling, eIF4E–cap interaction Co-IP

    PMID:20739757

    Open questions at the time
    • Did not define which spermatid mRNAs are directly affected
    • Did not test roles in non-germline tissues
  7. 2011 Medium

    Linked PAIP2's PABP-binding activity to tumor-suppressive function by showing it suppresses Ras-induced transformation in a PABP-binding-dependent manner.

    Evidence Soft-agar colony and focus formation assays with a PABP-binding mutant

    PMID:21957478

    Open questions at the time
    • Single study with cell-based transformation readouts only
    • No in vivo tumor evidence
    • Downstream mRNA targets not identified
  8. 2013 Medium

    Provided a structural rationale for repression by showing poly(A) bends PABP and that PAIP2 disrupts this bent conformation to inhibit poly(A) binding.

    Evidence Single-molecule real-time imaging of individual PABP molecules

    PMID:24293655

    Open questions at the time
    • Single method, single lab
    • Did not map the conformational change to specific RRM contacts
  9. 2013 Medium

    Assigned PAIP2 an antiviral role as an innate restriction factor that limits eIF4F assembly and viral protein synthesis during HCMV infection.

    Evidence siRNA depletion, Co-IP, viral replication and eIF4F assembly assays

    PMID:23964095

    Open questions at the time
    • Limited to HCMV context
    • Did not establish breadth across other viruses
  10. 2015 Medium

    Connected PAIP2 to miRNA function, showing transcriptional upregulation of PAIP2 via HNF4A enhances poly(A) shortening of miRNA-targeted mRNAs.

    Evidence ROCK inhibitor treatment, siRNA knockdown, miRNA reporter assays, Co-IP, nuclear fractionation

    PMID:26187994

    Open questions at the time
    • Mechanistic link is indirect
    • Did not define how PAIP2 promotes deadenylation mechanistically
  11. 2018 Medium

    Identified a nuclear, chromatin-associated pool of Paip2 recruited co-transcriptionally to active promoters via RNA-dependent interaction, extending PAIP2 beyond cytoplasmic translation.

    Evidence ChIP, nuclear fractionation, RNase treatment, immunofluorescence (Drosophila)

    PMID:29995569

    Open questions at the time
    • Drosophila ortholog only
    • Direct chromatin/RNA-binding partners not defined
  12. 2019 High

    Refined the termination model, showing PAIP2 blocks free PABP from stimulating eRF3a-dependent termination but loses this control once PABP is poly(A)-bound.

    Evidence In vitro translation termination reconstitution with purified components

    PMID:30992367

    Open questions at the time
    • Cellular relevance of premature termination control not established
  13. 2019 Medium

    Defined a nuclear Paip2 complex linking it to mRNA capping and Pol II transcription, showing cooperation with Cbp80 for proper CTD Ser5 phosphorylation.

    Evidence Co-IP, mass spectrometry, ChIP, CTD phosphorylation assay (Drosophila)

    PMID:31001806

    Open questions at the time
    • Drosophila ortholog only
    • Whether human PAIP2 has an equivalent nuclear role is untested
  14. 2022 High

    Resolved the molecular mechanism of poly(A) displacement, showing PAIP2A binds RRM2 first then displaces RRM3 from poly(A) with ~1 nM affinity comparable to poly(A) itself.

    Evidence Isothermal titration calorimetry and NMR structural analysis

    PMID:35307347

    Open questions at the time
    • Did not capture a full-length complex structure
    • Did not integrate eIF4G-competition mechanism structurally
  15. 2024 Medium

    Extended the nuclear function by showing Paip2 binds ENY2 and the TREX-2 complex and facilitates TREX-2 association with histone mRNPs at histone locus bodies.

    Evidence Yeast two-hybrid, in vitro pull-down, Co-IP, ChIP, RNAi, RNP fractionation (Drosophila)

    PMID:39707855

    Open questions at the time
    • Drosophila ortholog only
    • Functional consequence for histone mRNA processing not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the nuclear, co-transcriptional and TREX-2/histone-locus functions documented for the Drosophila ortholog are conserved in mammalian PAIP2 remains unresolved.
  • No direct evidence for human PAIP2 nuclear chromatin function
  • Relationship between cytoplasmic repressor and nuclear roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0045182 translation regulator activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 1
Partners
CBP80EDD/UBR5EIF4GENY2PABPC1PAIP1
Complex memberships
TREX-2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Paip2 is a novel PABP-interacting protein that represses translation both in vitro and in vivo by decreasing the affinity of PABP for polyadenylate RNA and disrupting the repeating structure of poly(A) RNP; it preferentially inhibits translation of poly(A)-containing mRNA but not cap- and eIF4G-independent HCV IRES-mediated translation. Paip2 also competes with Paip1 for PABP binding. In vitro translation assay, in vivo transfection, PABP-poly(A) binding assays, competition binding Molecular cell High 11172725
2001 Paip2 contains two binding sites for PABP: a 16-amino-acid C-terminal stretch and a central region. PABP also has two binding regions for Paip2: the RRM region and the C-terminal region. The stoichiometry is 2:1 (Paip2:PABP), with two independent Kd values of 0.66 nM and 74 nM. Only the central Paip2 fragment (binding PABP RRM with high affinity) inhibits PABP-poly(A) binding and translation. Biacore surface plasmon resonance, far-Western analysis, deletion mapping Molecular and cellular biology High 11438674
2006 Paip2 protein stability is regulated by the E3 ubiquitin ligase EDD: upon PABP depletion, Paip2 interacts with EDD, which ubiquitinates Paip2 and targets it for proteasomal degradation. Knockdown of EDD increases Paip2 stability. This establishes a homeostatic feedback loop whereby PABP levels regulate Paip2 turnover. RNAi knockdown of PABP and EDD, co-immunoprecipitation, ubiquitination assay, protein stability measurements The EMBO journal High 16601676
2006 Paip2 inhibits translation by a second mechanism: competing with eIF4G for binding to PABP, independent of its ability to disrupt PABP-poly(A) interaction. This was demonstrated by showing Paip2 inhibits translation when PABP is tethered to the 3' end of mRNA (bypassing poly(A) displacement). In vitro translation assay with tethered PABP, competition binding assay Proceedings of the National Academy of Sciences of the United States of America High 16772376
2006 Paip2B (a homolog of Paip2A sharing 59% identity) inhibits translation of capped and polyadenylated mRNAs both in vitro and in vivo by displacing PABP from the poly(A) tail, similar to Paip2A. However, Paip2A is more highly ubiquitinated than Paip2B and is degraded more rapidly by the proteasome. In vitro translation assay, in vivo overexpression, ubiquitination assay, proteasome inhibitor treatment RNA (New York, N.Y.) Medium 16804161
2010 Paip2a knockout mice are male-infertile; Paip2a/Paip2b double-KO mice show inhibited translation of mRNAs encoding proteins essential for spermiogenesis in late spermatids. This is caused by aberrant PABP overexpression (due to loss of Paip2-mediated homeostasis), which impairs eIF4E interaction with the 5' cap structure. Knockout mouse generation, polysome profiling, Western blot, co-immunoprecipitation (eIF4E-cap interaction assay) The Journal of clinical investigation High 20739757
2013 Poly(A) RNA induces a conformational change in PABP in which RRM1 comes into proximity with RRM4, bending the region between RRM2 and RRM3. Paip2 disrupts this bent structure, converting PABP to an extended conformation and thereby inhibiting PABP-poly(A) binding. Single-molecule real-time visualization (FRET/single-molecule imaging) of individual PABP molecules Nucleic acids research Medium 24293655
2013 During HCMV infection, Paip2 accumulates alongside PABP1 and EDD1 (via the viral UL38 mTORC1 activator), increases its association with PABP1, and acts as an innate restriction factor limiting viral protein synthesis. Depleting Paip2 restored eIF4F assembly and promoted viral replication without increasing PABP1. siRNA depletion of Paip2, co-immunoprecipitation, Western blot, viral replication assay, eIF4F assembly assay Genes & development Medium 23964095
2019 PAIP2 prevents translation termination at premature termination codons by inhibiting PABP activity at its C-terminal domain. PAIP2 inhibits free PABP-stimulated translation termination in vitro; however, once PABP is bound to the poly(A) tail, it becomes insensitive to PAIP2 suppression and efficiently activates translation termination via eRF3a. In vitro translation termination reconstitution assay, biochemical competition experiments with purified components The Journal of biological chemistry High 30992367
2019 In Drosophila, nuclear Paip2 is part of an ~300-kDa protein complex and interacts with the mRNA capping factor (Cbp80) and factors of RNA Pol II transcription initiation and early elongation. Paip2 functionally cooperates with Cbp80 to ensure proper Pol II CTD Ser5 phosphorylation at the promoter. Co-immunoprecipitation, mass spectrometry, ChIP, Pol II CTD phosphorylation assay (Drosophila) FEBS letters Medium 31001806
2018 In Drosophila, Paip2 is present in the nucleus and associates with chromatin at promoter regions of active genes via an RNA-dependent (indirect) interaction, suggesting Paip2 is recruited to mRNAs co-transcriptionally. Chromatin immunoprecipitation (ChIP), nuclear fractionation, RNase treatment, immunofluorescence in Drosophila tissues Cell cycle (Georgetown, Tex.) Medium 29995569
2022 Paip2A competitively binds the RRM2-RRM3 region of PABPC1 with Kd ~1 nM (comparable to poly(A) affinity). Mechanistically, Paip2A first binds RRM2 of poly(A)-bound PABPC1, and RRM2-anchored Paip2A then displaces RRM3 from poly(A), causing full dissociation of PABPC1 from the poly(A) tail. Isothermal titration calorimetry (ITC), NMR spectroscopy with structural analysis of RRM-ligand interactions The Journal of biological chemistry High 35307347
2015 ROCK inhibitor treatment increases PAIP2 expression via transcriptional upregulation by HNF4A, facilitated by increased ROCK1 nuclear localization and ROCK1 association with HNF4A. Elevated PAIP2 enhances poly(A) shortening of miRNA-targeted mRNAs, globally upregulating miRNA function. ROCK inhibitor treatment, siRNA knockdown of PAIP2 and ROCK1, reporter assays for miRNA function, co-immunoprecipitation (ROCK1-HNF4A), nuclear fractionation Nucleic acids research Medium 26187994
2011 Paip2 overexpression suppresses Ras(V12)-induced cellular transformation (colony formation in semi-solid matrix and focus formation), and this activity requires Paip2's ability to bind PABP. Soft-agar colony formation assay, focus formation assay, PABP-binding mutant of Paip2 PloS one Medium 21957478
2024 In Drosophila, Paip2 directly binds ENY2 in vitro and interacts with the ENY2-containing TREX-2 complex in vivo. Paip2 is present at the histone gene locus and histone locus bodies (HLBs). Paip2 knockdown decreases TREX-2 subunit association with histone mRNP particles, suggesting Paip2 facilitates TREX-2 binding to histone mRNPs. Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, ChIP, RNA interference knockdown, RNP particle fractionation (Drosophila) Molekuliarnaia biologiia Medium 39707855

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Translational repression by a novel partner of human poly(A) binding protein, Paip2. Molecular cell 183 11172725
2001 Dual interactions of the translational repressor Paip2 with poly(A) binding protein. Molecular and cellular biology 134 11438674
2006 Poly(A) binding protein (PABP) homeostasis is mediated by the stability of its inhibitor, Paip2. The EMBO journal 91 16601676
2006 A mechanism of translational repression by competition of Paip2 with eIF4G for poly(A) binding protein (PABP) binding. Proceedings of the National Academy of Sciences of the United States of America 76 16772376
2010 The poly(A)-binding protein partner Paip2a controls translation during late spermiogenesis in mice. The Journal of clinical investigation 59 20739757
2006 Regulation of poly(A) binding protein function in translation: Characterization of the Paip2 homolog, Paip2B. RNA (New York, N.Y.) 46 16804161
2019 Polyadenylate-binding protein-interacting proteins PAIP1 and PAIP2 affect translation termination. The Journal of biological chemistry 27 30992367
2013 A new role for the cellular PABP repressor Paip2 as an innate restriction factor capable of limiting productive cytomegalovirus replication. Genes & development 21 23964095
2012 PABP interacting protein 2A (PAIP2A) regulates specific key proteins during spermiogenesis in the mouse. Biology of reproduction 15 22190698
2013 Poly(A) RNA and Paip2 act as allosteric regulators of poly(A)-binding protein. Nucleic acids research 13 24293655
2019 Paip2 cooperates with Cbp80 at an active promoter and participates in RNA Polymerase II phosphorylation in Drosophila. FEBS letters 12 31001806
2015 ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression. Nucleic acids research 12 26187994
2018 Paip2 is localized to active promoters and loaded onto nascent mRNA in Drosophila. Cell cycle (Georgetown, Tex.) 10 29995569
2022 Paip2A inhibits translation by competitively binding to the RNA recognition motifs of PABPC1 and promoting its dissociation from the poly(A) tail. The Journal of biological chemistry 9 35307347
2011 Suppression of cellular transformation by poly (A) binding protein interacting protein 2 (Paip2). PloS one 7 21957478
2024 [Drosophila melanogaster Paip2 Binds ENY2 and Interacts with the TREX-2 Complex in Histone mRNP Particles]. Molekuliarnaia biologiia 1 39707855

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