Affinage

PAIP1

Polyadenylate-binding protein-interacting protein 1 · UniProt Q9H074

Length
479 aa
Mass
53.5 kDa
Annotated
2026-06-10
17 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAIP1 is a translational coactivator that enhances cap-dependent translation initiation by bridging the poly(A)-binding protein PABP with the initiation machinery (PMID:11997512, PMID:24396066). It engages PABP with high affinity (Kd ~1.9 nM) through two independent motifs, an N-terminal PAM2 and a C-terminal acidic PAM1 region, binding PABP's RRM1-2 and C-terminal domain at 1:1 stoichiometry (PMID:11997512). PAIP1 stimulation of initiation is gated by nutrient signaling: amino acid availability acting through the mTORC1/S6K1/2 axis drives S6K-dependent phosphorylation of eIF3 to promote the PAIP1-eIF3g interaction, and S6K inhibition reduces PAIP1-stimulated translation (PMID:24396066). Its abundance is controlled by the HECT E3 ligase WWP2, whose WW domain binds the PXXY residues of the PAM2 motif to ubiquitinate PAIP1 and target it for proteasomal degradation (PMID:25266661). Beyond initiation, PAIP1 modulates translation termination by competing with eRF3 for PABP's C-terminal domain and by directly binding eRF3 (PMID:30992367), and it relieves YBX2-mediated translational repression of spermiogenic mRNAs in testis (PMID:30295753). PAIP1 additionally functions in mRNA processing, binding GA-rich splicing enhancer motifs in pre-mRNAs and interacting with spliceosome components to regulate alternative splicing of cancer-related transcripts including VEGFA (PMID:39363305). The SARS-CoV/CoV-2 SUD macrodomain (Mac2) directly binds the middle domain of PAIP1 to selectively enhance viral protein synthesis, a structurally defined interaction (PMID:33876849). Loss of Paip1 in Drosophila reduces global translation and activates the PERK/eIF2α integrated stress response, driving apoptosis (PMID:37543696).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Establishing how PAIP1 physically engages the translation apparatus, this work defined the bipartite, high-affinity architecture of PAIP1-PABP recognition.

    Evidence Far-Western, GST pull-down, and surface plasmon resonance mapping two PABP-binding motifs (PAM1, PAM2) and reciprocal PABP sites

    PMID:11997512

    Open questions at the time
    • Does not establish how this interaction promotes mRNA circularization in vivo
    • Does not address regulation of the interaction
  2. 2014 High

    Linked PAIP1 activity to nutrient/growth signaling by showing its eIF3 association is controlled by the mTORC1/S6K pathway.

    Evidence Co-IP, S6K1/2 shRNA knockdown, in vitro kinase assay, and translation assays in cells

    PMID:24396066

    Open questions at the time
    • Exact eIF3 phosphosite(s) required not pinpointed
    • Quantitative contribution of eIF3g binding to initiation rate unresolved
  3. 2014 High

    Identified post-translational control of PAIP1 levels, explaining how the cell limits PAIP1-driven translation.

    Evidence Co-IP with domain mapping, ubiquitination assay, proteasome inhibition, and translation readout identifying WWP2 acting on the PAM2 PXXY motifs

    PMID:25266661

    Open questions at the time
    • Signals controlling WWP2 activity toward PAIP1 unknown
    • Deubiquitinase counteracting WWP2 not identified
  4. 2019 High

    Extended PAIP1's role from initiation to termination, showing it tunes termination by competing with eRF3 for PABP.

    Evidence In vitro reconstituted translation termination assay and biochemical binding measurements

    PMID:30992367

    Open questions at the time
    • Physiological conditions favoring termination inhibition versus poly(A)-bound activation not defined in cells
    • Cellular consequences of altered termination unquantified
  5. 2019 Medium

    Demonstrated a tissue-specific function by which PAIP1 derepresses stored mRNAs during spermiogenesis.

    Evidence Co-IP, immunofluorescence colocalization, sequential RNA-IP, and in vitro translation rescue of YBX2-repressed mRNAs in murine testes

    PMID:30295753

    Open questions at the time
    • In vivo Paip1-loss spermatogenesis phenotype not established
    • Direct PAIP1-YBX2 interaction interface not mapped
  6. 2021 High

    Resolved at atomic resolution how a coronaviral protein hijacks PAIP1 to favor viral translation.

    Evidence SEC, split-YFP, Co-IP, X-ray crystallography with SAXS validation, and replicon translation assay of the SARS-CoV SUD-Mac2/Paip1M complex

    PMID:33876849

    Open questions at the time
    • Mechanism by which SUD binding selectively favors viral over host mRNA not fully resolved
    • Effect on endogenous PAIP1 functions during infection unquantified
  7. 2023 Medium

    Established the organismal consequence of PAIP1 loss, connecting it to global translation capacity and stress-induced apoptosis.

    Evidence Drosophila genetic loss-of-function with epistasis, eIF2α phosphorylation, and 5'UTR reporter assays implicating PERK and Xrp1

    PMID:37543696

    Open questions at the time
    • Conservation of the ISR/Xrp1 axis in mammals untested
    • Direct molecular link between Paip1 loss and PERK activation unclear
  8. 2024 Medium

    Revealed a nuclear pre-mRNA processing role for PAIP1 beyond cytoplasmic translation, regulating alternative splicing.

    Evidence iRIP-seq, RNA-seq, interactome proteomics, and splicing reporter with GA-motif deletion showing VEGFA exon 6 regulation

    PMID:39363305

    Open questions at the time
    • Direct versus indirect splicing regulation not separated
    • Spliceosomal partner stoichiometry and recruitment mechanism unknown
  9. 2024 Low

    Connected PAIP1 to cancer cell proliferation through control of CCNE2 mRNA stability.

    Evidence RNA-seq, mRNA stability assay after knockdown, western blot, and xenograft in breast cancer cells

    PMID:39259041

    Open questions at the time
    • No direct PAIP1-CCNE2 mRNA interaction demonstrated
    • Mechanism linking PAIP1 to transcript stability not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAIP1's distinct activities — initiation enhancement, termination modulation, splicing, and mRNA stability — are coordinated and prioritized within a single cell remains unresolved.
  • No unified model integrating cytoplasmic translation and nuclear splicing roles
  • Determinants of transcript-specific selectivity unknown
  • Mammalian loss-of-function physiology largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 1
Partners
EIF3GGSPT1PABPC1WWP2YBX2

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Paip1 contains two independent PABP-binding motifs: PAM2 (a 15-amino-acid stretch in the N-terminus) and PAM1 (a larger C-terminal acidic-amino-acid-rich region). PABP reciprocally contains two Paip1-binding sites: one in RNA recognition motifs 1 and 2, and one in its C-terminal domain. Paip1 binds PABP with 1:1 stoichiometry and an apparent Kd of 1.9 nM. Far-Western, GST pull-down, and surface plasmon resonance assays Molecular and cellular biology High 11997512
2014 Paip1 interacts with the eIF3g subunit of eIF3, and this interaction is regulated by amino acids through the mTORC1/S6K1/2 signaling pathway. S6K1/2 phosphorylate eIF3 to promote Paip1-eIF3 interaction, enhancing translation initiation. Rapamycin, PP242, and S6K inhibitors impair the Paip1-eIF3 interaction, and S6K inhibition reduces Paip1-stimulated translation. Co-immunoprecipitation, shRNA knockdown of S6K1/2, in vitro phosphorylation assay, translation assays Molecular and cellular biology High 24396066
2014 The HECT-type E3 ubiquitin ligase WWP2 interacts with Paip1 via its WW domain binding to the PAM2 motif (specifically the two consecutive PXXY motifs) of Paip1, targeting Paip1 for ubiquitination and proteasomal degradation, thereby reducing Paip1-stimulated translation. Co-immunoprecipitation, ubiquitination assay, domain mapping, proteasome inhibitor treatment, translation assay Molecular and cellular biology High 25266661
2019 PAIP1 and PAIP2 inhibit PABP-dependent translation termination by competing with eRF3 for binding to the C-terminal domain of PABP. PAIP1 also directly binds eRF3 in solution, which stabilizes the post-termination complex. When PABP is bound to the poly(A) tail, it becomes insensitive to PAIPs and efficiently activates translation termination. In vitro translation termination assay, biochemical binding assays The Journal of biological chemistry High 30992367
2019 PAIP1 interacts with YBX2 in vitro and in vivo in murine testes, and PAIP1 co-localizes with YBX2 in round spermatids. PAIP1 relieves YBX2-mediated translational repression of spermiogenic mRNAs bearing the YBX2 target sequence, as demonstrated by sequential RNA immunoprecipitation and in vitro translation assays. Co-immunoprecipitation, colocalization (immunofluorescence), sequential RNA immunoprecipitation, in vitro translation assay Biology of reproduction Medium 30295753
2021 The SARS-CoV SUD (macrodomain II, Mac2) directly interacts with the middle domain of Paip1, and the crystal structure of this complex was determined by X-ray crystallography and validated by small-angle X-ray scattering. This interaction is conserved with SARS-CoV-2. SUD enhances viral (but not host) protein synthesis via Paip1 binding in replicon-transfected cells. Size-exclusion chromatography, split-YFP, co-immunoprecipitation, X-ray crystallography, small-angle X-ray scattering, replicon translation assay The EMBO journal High 33876849
2023 In Drosophila, loss of Paip1 causes reduced protein translation, activates the integrated stress response (ISR) via PERK-mediated eIF2α phosphorylation, and leads to apoptotic cell death. Loss of Paip1 also upregulates the transcription factor Xrp1, whose translation is enhanced via its 5'UTR, and Xrp1 in turn contributes to eIF2α phosphorylation and apoptosis. Genetic loss-of-function (Drosophila knockdown/knockout), epistasis analysis, eIF2α phosphorylation assay, 5'UTR reporter assay Cell death discovery Medium 37543696
2009 The middle domain of Paip1 (Paip1M) was crystallized and produced diffraction data to 2.2 Å resolution, providing structural information on this domain. X-ray crystallography (preliminary diffraction analysis) Acta crystallographica. Section F Low 19851022
2024 PAIP1 binds directly to pre-mRNAs/mRNAs with enrichment at coding regions and introns (GA-rich splicing enhancer motifs), interacts with spliceosome components and splicing factors (by proteomics), and regulates alternative splicing of cancer-related genes including VEGFA. Deletion of a PAIP1-binding GA-repeat motif reduced PAIP1-mediated suppression of VEGFA exon 6 inclusion. iRIP-seq (UV cross-linking RNA immunoprecipitation sequencing), RNA-seq, proteomic analysis of PAIP1-interacting proteins, splicing reporter with binding-site deletion BMC genomics Medium 39363305
2024 PAIP1 knockdown in breast cancer cells reduces cyclin E2 (CCNE2) expression by decreasing the mRNA stability of CCNE2, leading to cell cycle arrest and inhibition of proliferation. RNA-seq, mRNA stability assay (knockdown), western blot, xenograft model Molecular carcinogenesis Low 39259041

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Paip1 interacts with poly(A) binding protein through two independent binding motifs. Molecular and cellular biology 125 11997512
2021 The SARS-unique domain (SUD) of SARS-CoV and SARS-CoV-2 interacts with human Paip1 to enhance viral RNA translation. The EMBO journal 38 33876849
2014 Control of Paip1-eukayrotic translation initiation factor 3 interaction by amino acids through S6 kinase. Molecular and cellular biology 35 24396066
2019 Polyadenylate-binding protein-interacting proteins PAIP1 and PAIP2 affect translation termination. The Journal of biological chemistry 27 30992367
2014 Paip1, an effective stimulator of translation initiation, is targeted by WWP2 for ubiquitination and degradation. Molecular and cellular biology 17 25266661
2019 Role of Paip1 on angiogenesis and invasion in pancreatic cancer. Experimental cell research 14 30731074
2019 Murine PAIP1 stimulates translation of spermiogenic mRNAs stored by YBX2 via its interaction with YBX2†. Biology of reproduction 13 30295753
2019 Paip1 overexpression is involved in the progression of gastric cancer and predicts shorter survival of diagnosed patients. OncoTargets and therapy 13 31496746
2024 YAP1-activated ZNF131 promotes hepatocellular carcinoma cell proliferation through transcriptional regulation of PAIP1. Archives of biochemistry and biophysics 6 38341068
2023 Loss of Paip1 causes translation reduction and induces apoptotic cell death through ISR activation and Xrp1. Cell death discovery 6 37543696
2021 Upregulation of PAIP1 promotes the gallbladder tumorigenesis through regulating PLK1 level. Annals of translational medicine 5 34277791
2023 PAIP1 regulates expression of immune and inflammatory response associated genes at transcript level in liver cancer cell. PeerJ 3 37101794
2022 Circ_0005576 Exerts an Oncogenic Role in Cervical Cancer via miR-1305-Dependent Regulation of PAIP1. Reproductive sciences (Thousand Oaks, Calif.) 3 35378711
2024 PAIP1 binds to pre-mRNA and regulates alternative splicing of cancer pathway genes including VEGFA. BMC genomics 2 39363305
2022 PAIP1 is a novel oncogene in human hepatocellular carcinoma. Discover oncology 2 36436074
2009 Crystallization and preliminary X-ray diffraction analysis of the middle domain of Paip1. Acta crystallographica. Section F, Structural biology and crystallization communications 2 19851022
2024 Knockdown of PAIP1 Inhibits Breast Cancer Cell Proliferation by Regulating Cyclin E2 mRNA Stability. Molecular carcinogenesis 0 39259041

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