Affinage

CTIF

CBP80/20-dependent translation initiation factor · UniProt O43310

Length
598 aa
Mass
67.6 kDa
Annotated
2026-06-09
31 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CTIF (CBP80/20-dependent translation initiation factor) is a MIF4G domain-containing adaptor that drives the pioneer round of translation on newly exported, nuclear cap-binding complex (CBC)-bound mRNAs; depletion selectively blocks CBP80-dependent translation and abrogates nonsense-mediated mRNA decay (PMID:19648179). Mechanistically, CTIF bridges CBP80 to the ribosome-recruitment machinery by directly binding eIF3g, redistributing CBP80 between polysome and subpolysome fractions (PMID:22493286), and it independently recruits eIF4AIII to the 5' end of CBC-bound transcripts to unwind 5'UTR secondary structure and enhance translation (PMID:25313076). This activity is spatially restricted to the perinuclear region, where the DEAD-box helicase DDX19B holds CTIF translationally inactive until it is handed over to CBP80 on the cap of freshly exported mRNA, coupling mRNA export to localized CBC-dependent translation (PMID:34232997). Through its interaction with the stem-loop binding protein SLBP, CTIF couples histone mRNA translation to its regulated decay: hyperphosphorylated UPF1 competes with CTIF for SLBP, displacing CTIF and eIF3 to switch histone mRNPs from translation to degradation (PMID:23234701, PMID:25016523). Beyond translation, CTIF forms a trimeric CED complex with eEF1A1 and DCTN1 that recognizes misfolded polypeptides and delivers them to the aggresome via retrograde transport, sequestering CTIF and dampening translation under proteotoxic stress (PMID:28589942); this aggresome-targeting activity is positively regulated by hyperphosphorylated UPF1 and YTHDF2 (PMID:32561765, PMID:37803021) and negatively regulated by a PKR-driven TRIM28-CTIF interaction that also restricts viral proliferation (PMID:33783327). CTIF additionally inhibits HIV Gag synthesis by competing with Rev for CBP80 binding (PMID:33103564) and is a tankyrase PARylation substrate involved in centrosomal satellite distribution (PMID:29789535).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2009 High

    Established CTIF as a dedicated initiation factor for CBC-bound mRNAs, defining a CBP80/20-dependent translation pathway distinct from eIF4E-dependent translation and linking it to NMD.

    Evidence In vitro translation depletion/add-back, Co-IP with CBP80, siRNA knockdown, confocal microscopy

    PMID:19648179

    Open questions at the time
    • Did not define how CTIF couples the cap-bound complex to the ribosome
    • Perinuclear localization mechanism unresolved
  2. 2012 High

    Defined the molecular bridge by which CTIF recruits ribosomes, showing it is an adaptor linking CBP80/20 to eIF3 via eIF3g.

    Evidence Reciprocal Co-IP, polysome fractionation, dicistronic tethering reporter

    PMID:22493286

    Open questions at the time
    • Stoichiometry of CTIF-eIF3 interaction not resolved
    • Does not address 5'UTR structure handling
  3. 2012 Medium

    Extended CTIF's role to histone mRNA metabolism by identifying SLBP as a partner and localizing histone mRNA decay to CBC-bound transcripts.

    Evidence Yeast two-hybrid, Co-IP, polysome fractionation, mRNA stability assays

    PMID:23234701

    Open questions at the time
    • Direct CTIF-SLBP binding interface not mapped
    • Single lab, no reciprocal in vitro reconstitution
  4. 2013 Medium

    Provided structural rationale for CTIF as a histone mRNP platform by showing its MIF4G domain shares SLIP1-binding and dimerization residues.

    Evidence Crystal structures of SLIP1-SLBP and SLIP1-DBP5, pull-downs, sequence conservation

    PMID:23804756

    Open questions at the time
    • CTIF heterodimerization with SLIP1 inferred from homology, not directly demonstrated
    • No CTIF structure solved
  5. 2014 High

    Showed CTIF actively remodels mRNA structure by recruiting eIF4AIII to unwind 5'UTRs independently of deposited EJCs, mechanistically explaining enhanced CBC-dependent translation.

    Evidence Co-IP, in vitro reconstitution with recombinant proteins, polysome fractionation, tethering assay

    PMID:25313076

    Open questions at the time
    • Selectivity of eIF4AIII vs other helicases not addressed
    • Structural basis of CTIF-eIF4AIII interaction unknown
  6. 2014 Medium

    Resolved the translation-to-decay switch for histone mRNAs, showing hyperphosphorylated UPF1 competes with CTIF for SLBP to displace the translation apparatus.

    Evidence Co-IP competition, kinase inhibitor treatment, siRNA knockdown

    PMID:25016523

    Open questions at the time
    • Direct biochemical demonstration of competitive binding kinetics absent
    • Single lab
  7. 2017 High

    Revealed a translation-independent moonlighting role: CTIF assembles the trimeric CED complex with eEF1A1 and DCTN1 to deliver misfolded polypeptides to the aggresome, coupling proteotoxic stress to translational shutdown and apoptosis resistance.

    Evidence Reciprocal Co-IP, live-cell imaging, aggresome and apoptosis assays, siRNA

    PMID:28589942 PMID:28837386

    Open questions at the time
    • How CTIF recognizes misfolded substrates not defined
    • Switch between CT-complex and CED-complex membership not mechanistically resolved
  8. 2018 Medium

    Identified CTIF as a tankyrase PARylation substrate at centrosomes, implicating it in centrosomal satellite distribution.

    Evidence Genome-wide PAR-biosensor screen, transposon screen, live-cell imaging

    PMID:29789535

    Open questions at the time
    • PARylation site on CTIF not mapped
    • Functional consequence beyond satellite distribution unclear
  9. 2020 High

    Defined a positive regulator of aggresome targeting, showing hyperphosphorylated UPF1 binds the CED complex to increase the frequency and fidelity of CTIF aggregate transport.

    Evidence Co-IP, single-particle live-cell imaging, phosphomimetic mutants, apoptosis assay

    PMID:32561765

    Open questions at the time
    • Direct UPF1-CTIF contact within the complex not isolated
    • Link to UPF1's histone-mRNA role not integrated
  10. 2020 Medium

    Established an antiviral function: CTIF inhibits HIV Gag synthesis by binding Rev and competing with it for CBP80, sequestering Rev in the cytoplasm.

    Evidence Co-IP, siRNA knockdown, reporter assays, subcellular fractionation

    PMID:33103564

    Open questions at the time
    • N-terminal Rev-binding interface not structurally defined
    • In vivo relevance to viral replication not tested
  11. 2021 High

    Identified TRIM28 as a negative regulator of CTIF-mediated aggresome formation downstream of PKR signaling, linking the CED pathway to antiviral defense.

    Evidence Co-IP, PLA, phosphomimetic mutants, aggresome and viral proliferation assays

    PMID:33783327

    Open questions at the time
    • Whether TRIM28 binding blocks CED assembly or transport not distinguished
    • TRIM28-CTIF interface unmapped
  12. 2021 High

    Explained the spatial restriction of CTIF activity, showing DDX19B tethers CTIF in an inactive state and hands it to CBP80 on exported mRNA caps, coupling export to perinuclear translation.

    Evidence Co-IP, siRNA knockdown, reporter assays, confocal microscopy, polysome fractionation

    PMID:34232997

    Open questions at the time
    • Helicase-dependence of the handover step not biochemically dissected
    • Structural basis of CTIF-DDX19B interaction unknown
  13. 2023 Medium

    Identified YTHDF2 as an m6A-independent enhancer of aggresome targeting that strengthens dynein engagement of the CTIF-eEF1A1-DCTN1 complex via UPF1.

    Evidence Co-IP, live-cell imaging of aggresome dynamics, siRNA, apoptosis assay

    PMID:37803021

    Open questions at the time
    • CTIF studied as part of a pre-established complex, not the primary subject
    • Direct YTHDF2-CTIF contact not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CTIF physically switches between its CBC-dependent translation role and its aggresome-targeting role, and the structural basis for its multiple competing interactions (CBP80, eIF3g, eIF4AIII, SLBP, DDX19B, Rev, TRIM28), remains undefined.
  • No high-resolution structure of CTIF itself
  • Mechanism partitioning CTIF between translation and proteostasis pools unresolved
  • Physiological/disease contexts of these activities not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9612973 Autophagy 3
Complex memberships
CBP80/20-dependent translation initiation complex (CBC-CTIF)CED complex (CTIF-eEF1A1-DCTN1)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 CTIF contains a MIF4G domain and directly interacts with CBP80 (nuclear cap-binding protein 80), forming part of the CBP80/20-dependent translation initiation complex. Depletion of endogenous CTIF from an in vitro translation system selectively blocks translation of CBP80-bound mRNAs, while addition of purified CTIF restores it. CTIF localizes to the perinuclear region by confocal microscopy. Down-regulation of CTIF also abrogates nonsense-mediated mRNA decay (NMD). In vitro translation reconstitution with recombinant protein add-back, co-immunoprecipitation (Co-IP), siRNA knockdown, confocal microscopy Genes & development High 19648179
2012 CTIF specifically interacts with eIF3g (a component of the eIF3 ribosome-recruitment complex) and serves as an adaptor protein bridging CBP80/20 to eIF3 during CBC-dependent translation. Down-regulation of CTIF redistributes CBP80 from polysome fractions to subpolysome fractions without affecting eIF4E distribution. Artificial tethering of CTIF to an intercistronic region of dicistronic mRNA drives downstream cistron translation in an eIF3-dependent manner. Co-immunoprecipitation, siRNA knockdown with polysome fractionation, tethering assay with dicistronic reporter The Journal of biological chemistry High 22493286
2012 CTIF interacts with stem-loop binding protein (SLBP) — identified via yeast two-hybrid screening — and SLBP preferentially associates with the CBC-dependent translation (CT) complex of histone mRNAs. Rapid degradation of histone mRNA upon inhibition of DNA replication largely occurs on CBP80/20-bound (CT) mRNAs rather than eIF4E-bound mRNAs. Yeast two-hybrid screening, co-immunoprecipitation, polysome fractionation, mRNA stability assays Nucleic acids research Medium 23234701
2013 The MIF4G domain of CTIF is structurally related to SLIP1 and shares conserved SBM (SLIP1-binding motif)-binding and homodimerization residues, suggesting CTIF can form a SLIP1-CTIF heterodimer as a platform to bridge SLBP with translation initiation factors. Crystal structure of SLIP1-SLBP (2.5 Å) and SLIP1-DBP5 (3.25 Å), pull-down assays, sequence conservation analysis Nucleic acids research Medium 23804756
2014 eIF4AIII (an EJC component) is recruited to the 5'-end of CBC-bound mRNAs through direct interaction with CTIF, independently of deposited EJCs. This recruitment promotes unwinding of 5'UTR secondary structures and enhances CBC-dependent translation both in vivo and in vitro. Co-immunoprecipitation, in vitro reconstitution with recombinant proteins, polysome fractionation, tethering assay Proceedings of the National Academy of Sciences of the United States of America High 25313076
2014 CTIF interacts with SLBP and this interaction is important for efficient histone mRNA translation. Upon inhibition of DNA replication or at the end of S phase, hyperphosphorylated UPF1 (phosphorylated by ATR and DNA-PK) competes with CTIF for SLBP binding, displacing CTIF and eIF3 from the SLBP-containing histone mRNP, thereby switching histone mRNA from translation to degradation mode. Co-immunoprecipitation, competition binding assay, siRNA knockdown, kinase inhibitor treatment Nucleic acids research Medium 25016523
2017 CTIF forms a trimeric CED complex with eEF1A1 and DCTN1 (dynactin subunit 1) that selectively recognizes misfolded polypeptides and targets them to the aggresome via retrograde transport. When UPS is impaired, CTIF is sequestered into the aggresome, which reduces CBC-dependent translation and renders cells more resistant to proteotoxic-stress-induced apoptosis. Co-immunoprecipitation, live-cell imaging, siRNA knockdown, aggresome formation assay, apoptosis assay Nature communications High 28589942
2017 The CED complex (CTIF-eEF1A1-DCTN1) functions as aggresome-targeting machinery; CTIF release from the CT (CBC-dependent translation) complex accompanies aggresomal targeting, establishing crosstalk between translational inhibition and aggresome formation under proteotoxic stress. Co-immunoprecipitation, imaging of aggresome formation, translation assays (review/commentary with direct reference to experimental findings of PMID:28589942) Autophagy Medium 28837386
2018 CTIF is a novel PARylation target of tankyrase enzymes at the centrosomal region, identified by a genome-wide PAR-biosensor screen. CTIF plays a role in the distribution of centrosomal satellites. Bimolecular fluorescent complementation PAR biosensor, transposon-mediated genome-wide screen, live-cell imaging Nature communications Medium 29789535
2020 Hyperphosphorylated UPF1 promotes aggresome formation by interacting with the CTIF-eEF1A1-DCTN1 (CED) complex. Single-particle visualization shows UPF1 increases both the frequency and fidelity of movement of CTIF aggregates toward the aggresome. UPF1 hyperphosphorylation suppresses proteotoxic-stress-induced apoptosis. Co-immunoprecipitation, single-particle live-cell imaging, siRNA knockdown, phosphomimetic mutant analysis, apoptosis assay Nature communications High 32561765
2020 CTIF inhibits HIV-1 and HIV-2 Gag synthesis from the full-length viral RNA. CTIF associates with HIV-1 Rev through its N-terminal domain and is recruited onto the full-length RNA ribonucleoprotein complex, where it interferes with Gag synthesis. CTIF also induces cytoplasmic accumulation of Rev, impeding Rev's association with CBP80. Conversely, Rev competes with CTIF for CBP80 binding. Co-immunoprecipitation, siRNA knockdown, reporter assays, subcellular fractionation RNA biology Medium 33103564
2021 TRIM28 directly interacts with CTIF and acts as a negative regulator of aggresome formation: the TRIM28-CTIF interaction leads to inefficient aggresomal targeting of misfolded polypeptides. Viral infection (influenza A) or poly I:C treatment triggers phosphorylation of TRIM28 at S473 by double-stranded RNA-activated protein kinase (PKR/EIF2AK2), which promotes TRIM28-CTIF association, inhibits aggresome formation, and suppresses viral proliferation. Co-immunoprecipitation, proximity ligation assay (PLA), siRNA knockdown, phosphomimetic mutants, aggresome formation assay, viral proliferation assay Autophagy High 33783327
2021 CTIF is tethered in a translationally incompetent state to the perinuclear region by the DEAD-box helicase DDX19B. Upon mRNA export, DDX19B hands CTIF over to CBP80 associated with the 5'-cap of newly exported mRNA, forming the CBP80-CTIF complex that initiates CBC-dependent translation at the perinuclear region. Disrupting the CTIF-DDX19B interaction leads to uncontrolled CBC-dependent translation throughout the cytosol and dysregulates NMD. Co-immunoprecipitation, siRNA knockdown, reporter assays, confocal microscopy, polysome fractionation Nucleic acids research High 34232997
2023 YTHDF2 is recruited to the misfolded polypeptide-associated complex containing UPF1, CTIF, eEF1A1, and DCTN1 through its interaction with UPF1 (m6A-independent). YTHDF2 increases the interaction between dynein motor protein and the misfolded polypeptide-associated complex, facilitating movement of misfolded polypeptides toward aggresomes. Co-immunoprecipitation, siRNA knockdown, live-cell imaging of aggresome dynamics, apoptosis assay Nature communications Medium 37803021

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 A new MIF4G domain-containing protein, CTIF, directs nuclear cap-binding protein CBP80/20-dependent translation. Genes & development 101 19648179
2014 eIF4AIII enhances translation of nuclear cap-binding complex-bound mRNAs by promoting disruption of secondary structures in 5'UTR. Proceedings of the National Academy of Sciences of the United States of America 62 25313076
2012 Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g. The Journal of biological chemistry 45 22493286
2017 Misfolded polypeptides are selectively recognized and transported toward aggresomes by a CED complex. Nature communications 40 28589942
2017 Crosstalk between translation and the aggresome-autophagy pathway. Autophagy 34 28837386
2014 The mRNP remodeling mediated by UPF1 promotes rapid degradation of replication-dependent histone mRNA. Nucleic acids research 33 25016523
2013 Structural and biochemical studies of SLIP1-SLBP identify DBP5 and eIF3g as SLIP1-binding proteins. Nucleic acids research 32 23804756
2012 Rapid degradation of replication-dependent histone mRNAs largely occurs on mRNAs bound by nuclear cap-binding proteins 80 and 20. Nucleic acids research 31 23234701
2018 Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets. Nature communications 30 29789535
2020 Nonsense-mediated mRNA decay factor UPF1 promotes aggresome formation. Nature communications 29 32561765
2019 A genome-wide association study of gestational diabetes mellitus in Chinese women. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 29 31269844
2019 The Effects of Epigallocatechin Gallate (EGCG) on Pulmonary Fibroblasts of Idiopathic Pulmonary Fibrosis (IPF)-A Next-Generation Sequencing and Bioinformatic Approach. International journal of molecular sciences 27 31013581
1983 Endogenous retrovirus expression in stimulated murine lymphocytes. Identification of a new locus controlling mitogen induction of a defective virus. The Journal of experimental medicine 23 6189943
2021 UPF1: From mRNA Surveillance to Protein Quality Control. Biomedicines 22 34440199
2014 Degradation of oligouridylated histone mRNAs: see UUUUU and goodbye. Wiley interdisciplinary reviews. RNA 20 24692427
1979 Long term follow-up of combination chemotherapy-radiotherapy of stage III Hodgkin's disease: a Cancer and Acute Leukemia Group B study. Cancer 18 445326
2021 TRIM28 functions as a negative regulator of aggresome formation. Autophagy 16 33783327
2019 Reduction of aluminum ion neurotoxicity through a small peptide application - NAP treatment of Alzheimer's disease. Journal of food and drug analysis 16 30987727
2021 Translation mediated by the nuclear cap-binding complex is confined to the perinuclear region via a CTIF-DDX19B interaction. Nucleic acids research 15 34232997
2023 YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner. Nature communications 11 37803021
2023 Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study. Annals of neurology 9 37528491
2020 CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev. RNA biology 9 33103564
2015 Identification of biomarkers for metastatic osteosarcoma based on DNA microarray data. Neoplasma 9 25866217
2019 Genome-wide association study identifies genomic loci associated with flight reaction in cattle. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 5 31828846
2022 Recent Advances in the Endoscopic Management of Gastro-esophageal Reflux Disorder: A Review of Literature. Cureus 4 35784968
2016 Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate. Frontiers in genetics 3 27242896
2015 Association of SNPs in LCP1 and CTIF with hearing in 11 year old children: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and the G-EAR consortium. BMC medical genomics 3 26264041
2021 Association of Single Nucleotide Polymorphisms on Locus 18q21.1 in the Etiology of Nonsyndromic Cleft Lip Palate (NSCLP) in Indian Multiplex Families. Global medical genetics 2 33748821
2020 [Comparative study of the human keratinocytes proteome of the HaCaT line: identification of proteins encoded by genes of 18 chromosomes under the influence of detergents]. Biomeditsinskaia khimiia 2 33372905
2026 The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region. Life science alliance 0 41807047
2025 Association between methylation quantitative trait loci and colorectal cancer risk, survival and cancer recurrence. British journal of cancer 0 40506516

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