{"gene":"CTIF","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2009,"finding":"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).","method":"In vitro translation reconstitution with recombinant protein add-back, co-immunoprecipitation (Co-IP), siRNA knockdown, confocal microscopy","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with depletion and add-back, Co-IP, and multiple orthogonal methods in founding paper","pmids":["19648179"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown with polysome fractionation, tethering assay with dicistronic reporter","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, polysome fractionation, and functional tethering assay, single lab with multiple orthogonal methods","pmids":["22493286"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Yeast two-hybrid screening, co-immunoprecipitation, polysome fractionation, mRNA stability assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and fractionation, single lab","pmids":["23234701"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Crystal structure of SLIP1-SLBP (2.5 Å) and SLIP1-DBP5 (3.25 Å), pull-down assays, sequence conservation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution crystal structure with conservation analysis but CTIF heterodimerization itself not directly demonstrated, only inferred from structural homology","pmids":["23804756"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, in vitro reconstitution with recombinant proteins, polysome fractionation, tethering assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus Co-IP and polysome fractionation, multiple orthogonal methods, single lab","pmids":["25313076"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, competition binding assay, siRNA knockdown, kinase inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP competition assay plus pharmacological kinase inhibition and siRNA, single lab, two orthogonal approaches","pmids":["25016523"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, live-cell imaging, siRNA knockdown, aggresome formation assay, apoptosis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying trimeric complex, live imaging, functional knockdown with apoptosis readout, multiple orthogonal methods","pmids":["28589942"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, imaging of aggresome formation, translation assays (review/commentary with direct reference to experimental findings of PMID:28589942)","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primarily a review/commentary reiterating findings from PMID:28589942; no new experimental data, treated as corroborating context","pmids":["28837386"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Bimolecular fluorescent complementation PAR biosensor, transposon-mediated genome-wide screen, live-cell imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel genome-wide screen with biosensor identifies CTIF PARylation by tankyrase, but mechanistic follow-up on CTIF specifically is limited to centrosomal satellite distribution","pmids":["29789535"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, single-particle live-cell imaging, siRNA knockdown, phosphomimetic mutant analysis, apoptosis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, single-particle imaging, phosphomimetic mutants, and apoptosis readout; multiple orthogonal methods in single lab","pmids":["32561765"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, reporter assays, subcellular fractionation","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying N-terminal domain interaction, siRNA knockdown with Gag synthesis readout, competition binding, single lab","pmids":["33103564"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, proximity ligation assay (PLA), siRNA knockdown, phosphomimetic mutants, aggresome formation assay, viral proliferation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct Co-IP plus PLA, phosphomimetic mutants, and functional viral proliferation readout, multiple orthogonal methods in single lab","pmids":["33783327"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, reporter assays, confocal microscopy, polysome fractionation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct interaction, functional knockdown showing spatial dysregulation of CT and NMD, multiple orthogonal approaches, single lab","pmids":["34232997"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, live-cell imaging of aggresome dynamics, apoptosis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live imaging and functional knockdown, but CTIF's role here is as part of a pre-established complex rather than the primary subject","pmids":["37803021"],"is_preprint":false}],"current_model":"CTIF (CBP80/20-dependent translation initiation factor) is a MIF4G domain-containing protein that localizes to the perinuclear region, where it is held in a translationally inactive state by DDX19B until CBP80-capped newly exported mRNAs recruit it to initiate CBC-dependent translation by bridging CBP80 to eIF3g for ribosome recruitment and by recruiting eIF4AIII to unwind 5'UTR secondary structures; it also participates in NMD, histone mRNA translation and regulated degradation (via SLBP interaction displaced by hyperphosphorylated UPF1), and a separate function as part of the CTIF-eEF1A1-DCTN1 (CED) aggresome-targeting complex that selectively recognizes and transports misfolded polypeptides to the aggresome—a process negatively regulated by TRIM28-CTIF interaction and positively regulated by UPF1 and YTHDF2—while also being a substrate of tankyrase-mediated PARylation at centrosomal satellites and inhibiting HIV Gag synthesis by competing with Rev for CBP80 binding."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2009,"claim":"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","pmids":["19648179"],"confidence":"High","gaps":["Did not define how CTIF couples the cap-bound complex to the ribosome","Perinuclear localization mechanism unresolved"]},{"year":2012,"claim":"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","pmids":["22493286"],"confidence":"High","gaps":["Stoichiometry of CTIF-eIF3 interaction not resolved","Does not address 5'UTR structure handling"]},{"year":2012,"claim":"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","pmids":["23234701"],"confidence":"Medium","gaps":["Direct CTIF-SLBP binding interface not mapped","Single lab, no reciprocal in vitro reconstitution"]},{"year":2013,"claim":"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","pmids":["23804756"],"confidence":"Medium","gaps":["CTIF heterodimerization with SLIP1 inferred from homology, not directly demonstrated","No CTIF structure solved"]},{"year":2014,"claim":"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","pmids":["25313076"],"confidence":"High","gaps":["Selectivity of eIF4AIII vs other helicases not addressed","Structural basis of CTIF-eIF4AIII interaction unknown"]},{"year":2014,"claim":"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","pmids":["25016523"],"confidence":"Medium","gaps":["Direct biochemical demonstration of competitive binding kinetics absent","Single lab"]},{"year":2017,"claim":"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","pmids":["28589942","28837386"],"confidence":"High","gaps":["How CTIF recognizes misfolded substrates not defined","Switch between CT-complex and CED-complex membership not mechanistically resolved"]},{"year":2018,"claim":"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","pmids":["29789535"],"confidence":"Medium","gaps":["PARylation site on CTIF not mapped","Functional consequence beyond satellite distribution unclear"]},{"year":2020,"claim":"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","pmids":["32561765"],"confidence":"High","gaps":["Direct UPF1-CTIF contact within the complex not isolated","Link to UPF1's histone-mRNA role not integrated"]},{"year":2020,"claim":"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","pmids":["33103564"],"confidence":"Medium","gaps":["N-terminal Rev-binding interface not structurally defined","In vivo relevance to viral replication not tested"]},{"year":2021,"claim":"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","pmids":["33783327"],"confidence":"High","gaps":["Whether TRIM28 binding blocks CED assembly or transport not distinguished","TRIM28-CTIF interface unmapped"]},{"year":2021,"claim":"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","pmids":["34232997"],"confidence":"High","gaps":["Helicase-dependence of the handover step not biochemically dissected","Structural basis of CTIF-DDX19B interaction unknown"]},{"year":2023,"claim":"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","pmids":["37803021"],"confidence":"Medium","gaps":["CTIF studied as part of a pre-established complex, not the primary subject","Direct YTHDF2-CTIF contact not shown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,9,11]}],"complexes":["CBP80/20-dependent translation initiation complex (CBC-CTIF)","CED complex (CTIF-eEF1A1-DCTN1)"],"partners":["CBP80","EIF3G","EIF4A3","SLBP","DDX19B","EEF1A1","DCTN1","TRIM28"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43310","full_name":"CBP80/20-dependent translation initiation factor","aliases":[],"length_aa":598,"mass_kda":67.6,"function":"Specifically required for the pioneer round of mRNA translation mediated by the cap-binding complex (CBC), that takes place during or right after mRNA export via the nuclear pore complex (NPC). Acts via its interaction with the NCBP1/CBP80 component of the CBC complex and recruits the 40S small subunit of the ribosome via eIF3. In contrast, it is not involved in steady state translation, that takes place when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. Also required for nonsense-mediated mRNA decay (NMD), the pioneer round of mRNA translation mediated by the cap-binding complex playing a central role in nonsense-mediated mRNA decay (NMD)","subcellular_location":"Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/O43310/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTIF","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTIF","total_profiled":1310},"omim":[{"mim_id":"613178","title":"CAP-BINDING COMPLEX-DEPENDENT TRANSLATION INITIATION FACTOR; CTIF","url":"https://www.omim.org/entry/613178"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTIF"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0427"]},"alphafold":{"accession":"O43310","domains":[{"cath_id":"1.25.40.180","chopping":"368-466","consensus_level":"medium","plddt":90.7713,"start":368,"end":466},{"cath_id":"1.25.40.180","chopping":"490-598","consensus_level":"medium","plddt":94.1361,"start":490,"end":598}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43310","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43310-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43310-F1-predicted_aligned_error_v6.png","plddt_mean":62.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTIF","jax_strain_url":"https://www.jax.org/strain/search?query=CTIF"},"sequence":{"accession":"O43310","fasta_url":"https://rest.uniprot.org/uniprotkb/O43310.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43310/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43310"}},"corpus_meta":[{"pmid":"19648179","id":"PMC_19648179","title":"A new MIF4G domain-containing protein, CTIF, directs nuclear cap-binding protein CBP80/20-dependent translation.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19648179","citation_count":101,"is_preprint":false},{"pmid":"25313076","id":"PMC_25313076","title":"eIF4AIII enhances translation of nuclear cap-binding complex-bound mRNAs by promoting disruption of secondary structures in 5'UTR.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25313076","citation_count":62,"is_preprint":false},{"pmid":"22493286","id":"PMC_22493286","title":"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.","date":"2012","source":"The Journal of biological 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/33103564","citation_count":9,"is_preprint":false},{"pmid":"25866217","id":"PMC_25866217","title":"Identification of biomarkers for metastatic osteosarcoma based on DNA microarray data.","date":"2015","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/25866217","citation_count":9,"is_preprint":false},{"pmid":"37528491","id":"PMC_37528491","title":"Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study.","date":"2023","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37528491","citation_count":9,"is_preprint":false},{"pmid":"31828846","id":"PMC_31828846","title":"Genome-wide association study identifies genomic loci associated with flight reaction in cattle.","date":"2019","source":"Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/31828846","citation_count":5,"is_preprint":false},{"pmid":"35784968","id":"PMC_35784968","title":"Recent Advances in the Endoscopic Management of Gastro-esophageal Reflux Disorder: A Review of Literature.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/35784968","citation_count":4,"is_preprint":false},{"pmid":"26264041","id":"PMC_26264041","title":"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.","date":"2015","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/26264041","citation_count":3,"is_preprint":false},{"pmid":"27242896","id":"PMC_27242896","title":"Fine-Mapping of 18q21.1 Locus Identifies Single Nucleotide Polymorphisms Associated with Nonsyndromic Cleft Lip with or without Cleft Palate.","date":"2016","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27242896","citation_count":3,"is_preprint":false},{"pmid":"33748821","id":"PMC_33748821","title":"Association of Single Nucleotide Polymorphisms on Locus 18q21.1 in the Etiology of Nonsyndromic Cleft Lip Palate (NSCLP) in Indian Multiplex Families.","date":"2021","source":"Global medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33748821","citation_count":2,"is_preprint":false},{"pmid":"33372905","id":"PMC_33372905","title":"[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].","date":"2020","source":"Biomeditsinskaia khimiia","url":"https://pubmed.ncbi.nlm.nih.gov/33372905","citation_count":2,"is_preprint":false},{"pmid":"40506516","id":"PMC_40506516","title":"Association between methylation quantitative trait loci and colorectal cancer risk, survival and cancer recurrence.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40506516","citation_count":0,"is_preprint":false},{"pmid":"41807047","id":"PMC_41807047","title":"The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region.","date":"2026","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/41807047","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.18.624084","title":"The CDKL5 kinase undergoes liquid-liquid phase separation driven by a serine-rich C-terminal region and impaired by neurodevelopmental disease-related truncations","date":"2024-11-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.18.624084","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17501,"output_tokens":3993,"usd":0.056199,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23082,"output_tokens":8218,"usd":0.241952,"resynth_parse_fail":true,"stage2_stop_reason":"end_turn"},"total_usd":0.298151,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical CTIF protein (CBP80/20-dependent translation initiation factor, KIAA0427). I'll classify each paper:\n\n- Papers [1]-[10], [14]-[15], [17], [19]-[21]: About canonical CTIF (CBP80/20-dependent translation initiation factor) — INCLUDE\n- Papers [7]: About SLIP1/CTIF structural relationship — INCLUDE\n- Papers [11], [12], [13], [16], [18], [22]-[30]: GWAS, biomarker, expression, clinical, or unrelated studies — EXCLUDE\n- Papers [31], [32]: About CDKL5 — \"CTIF\" here means \"CTD internal fragment,\" a completely different protein context — EXCLUDE (symbol collision/terminology collision)\n\nNow extracting mechanistic discoveries:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"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).\",\n      \"method\": \"In vitro translation reconstitution with recombinant protein add-back, co-immunoprecipitation (Co-IP), siRNA knockdown, confocal microscopy\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with depletion and add-back, Co-IP, and multiple orthogonal methods in founding paper\",\n      \"pmids\": [\"19648179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with polysome fractionation, tethering assay with dicistronic reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, polysome fractionation, and functional tethering assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22493286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, polysome fractionation, mRNA stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP and fractionation, single lab\",\n      \"pmids\": [\"23234701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure of SLIP1-SLBP (2.5 Å) and SLIP1-DBP5 (3.25 Å), pull-down assays, sequence conservation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution crystal structure with conservation analysis but CTIF heterodimerization itself not directly demonstrated, only inferred from structural homology\",\n      \"pmids\": [\"23804756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro reconstitution with recombinant proteins, polysome fractionation, tethering assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus Co-IP and polysome fractionation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"25313076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, siRNA knockdown, kinase inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP competition assay plus pharmacological kinase inhibition and siRNA, single lab, two orthogonal approaches\",\n      \"pmids\": [\"25016523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, siRNA knockdown, aggresome formation assay, apoptosis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying trimeric complex, live imaging, functional knockdown with apoptosis readout, multiple orthogonal methods\",\n      \"pmids\": [\"28589942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, imaging of aggresome formation, translation assays (review/commentary with direct reference to experimental findings of PMID:28589942)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primarily a review/commentary reiterating findings from PMID:28589942; no new experimental data, treated as corroborating context\",\n      \"pmids\": [\"28837386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Bimolecular fluorescent complementation PAR biosensor, transposon-mediated genome-wide screen, live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel genome-wide screen with biosensor identifies CTIF PARylation by tankyrase, but mechanistic follow-up on CTIF specifically is limited to centrosomal satellite distribution\",\n      \"pmids\": [\"29789535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, single-particle live-cell imaging, siRNA knockdown, phosphomimetic mutant analysis, apoptosis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, single-particle imaging, phosphomimetic mutants, and apoptosis readout; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32561765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter assays, subcellular fractionation\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying N-terminal domain interaction, siRNA knockdown with Gag synthesis readout, competition binding, single lab\",\n      \"pmids\": [\"33103564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PLA), siRNA knockdown, phosphomimetic mutants, aggresome formation assay, viral proliferation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP plus PLA, phosphomimetic mutants, and functional viral proliferation readout, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"33783327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter assays, confocal microscopy, polysome fractionation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct interaction, functional knockdown showing spatial dysregulation of CT and NMD, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"34232997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, live-cell imaging of aggresome dynamics, apoptosis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus live imaging and functional knockdown, but CTIF's role here is as part of a pre-established complex rather than the primary subject\",\n      \"pmids\": [\"37803021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTIF (CBP80/20-dependent translation initiation factor) is a MIF4G domain-containing protein that localizes to the perinuclear region, where it is held in a translationally inactive state by DDX19B until CBP80-capped newly exported mRNAs recruit it to initiate CBC-dependent translation by bridging CBP80 to eIF3g for ribosome recruitment and by recruiting eIF4AIII to unwind 5'UTR secondary structures; it also participates in NMD, histone mRNA translation and regulated degradation (via SLBP interaction displaced by hyperphosphorylated UPF1), and a separate function as part of the CTIF-eEF1A1-DCTN1 (CED) aggresome-targeting complex that selectively recognizes and transports misfolded polypeptides to the aggresome—a process negatively regulated by TRIM28-CTIF interaction and positively regulated by UPF1 and YTHDF2—while also being a substrate of tankyrase-mediated PARylation at centrosomal satellites and inhibiting HIV Gag synthesis by competing with Rev for CBP80 binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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 [#0]. Mechanistically, CTIF bridges CBP80 to the ribosome-recruitment machinery by directly binding eIF3g, redistributing CBP80 between polysome and subpolysome fractions [#1], and it independently recruits eIF4AIII to the 5' end of CBC-bound transcripts to unwind 5'UTR secondary structure and enhance translation [#4]. 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 [#12]. 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 [#2, #5]. 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 [#6]; this aggresome-targeting activity is positively regulated by hyperphosphorylated UPF1 and YTHDF2 [#9, #13] and negatively regulated by a PKR-driven TRIM28-CTIF interaction that also restricts viral proliferation [#11]. CTIF additionally inhibits HIV Gag synthesis by competing with Rev for CBP80 binding [#10] and is a tankyrase PARylation substrate involved in centrosomal satellite distribution [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro translation depletion/add-back, Co-IP with CBP80, siRNA knockdown, confocal microscopy\",\n      \"pmids\": [\"19648179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how CTIF couples the cap-bound complex to the ribosome\", \"Perinuclear localization mechanism unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the molecular bridge by which CTIF recruits ribosomes, showing it is an adaptor linking CBP80/20 to eIF3 via eIF3g.\",\n      \"evidence\": \"Reciprocal Co-IP, polysome fractionation, dicistronic tethering reporter\",\n      \"pmids\": [\"22493286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of CTIF-eIF3 interaction not resolved\", \"Does not address 5'UTR structure handling\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended CTIF's role to histone mRNA metabolism by identifying SLBP as a partner and localizing histone mRNA decay to CBC-bound transcripts.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, polysome fractionation, mRNA stability assays\",\n      \"pmids\": [\"23234701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CTIF-SLBP binding interface not mapped\", \"Single lab, no reciprocal in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided structural rationale for CTIF as a histone mRNP platform by showing its MIF4G domain shares SLIP1-binding and dimerization residues.\",\n      \"evidence\": \"Crystal structures of SLIP1-SLBP and SLIP1-DBP5, pull-downs, sequence conservation\",\n      \"pmids\": [\"23804756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CTIF heterodimerization with SLIP1 inferred from homology, not directly demonstrated\", \"No CTIF structure solved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CTIF actively remodels mRNA structure by recruiting eIF4AIII to unwind 5'UTRs independently of deposited EJCs, mechanistically explaining enhanced CBC-dependent translation.\",\n      \"evidence\": \"Co-IP, in vitro reconstitution with recombinant proteins, polysome fractionation, tethering assay\",\n      \"pmids\": [\"25313076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of eIF4AIII vs other helicases not addressed\", \"Structural basis of CTIF-eIF4AIII interaction unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the translation-to-decay switch for histone mRNAs, showing hyperphosphorylated UPF1 competes with CTIF for SLBP to displace the translation apparatus.\",\n      \"evidence\": \"Co-IP competition, kinase inhibitor treatment, siRNA knockdown\",\n      \"pmids\": [\"25016523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration of competitive binding kinetics absent\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal Co-IP, live-cell imaging, aggresome and apoptosis assays, siRNA\",\n      \"pmids\": [\"28589942\", \"28837386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CTIF recognizes misfolded substrates not defined\", \"Switch between CT-complex and CED-complex membership not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified CTIF as a tankyrase PARylation substrate at centrosomes, implicating it in centrosomal satellite distribution.\",\n      \"evidence\": \"Genome-wide PAR-biosensor screen, transposon screen, live-cell imaging\",\n      \"pmids\": [\"29789535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PARylation site on CTIF not mapped\", \"Functional consequence beyond satellite distribution unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a positive regulator of aggresome targeting, showing hyperphosphorylated UPF1 binds the CED complex to increase the frequency and fidelity of CTIF aggregate transport.\",\n      \"evidence\": \"Co-IP, single-particle live-cell imaging, phosphomimetic mutants, apoptosis assay\",\n      \"pmids\": [\"32561765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct UPF1-CTIF contact within the complex not isolated\", \"Link to UPF1's histone-mRNA role not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established an antiviral function: CTIF inhibits HIV Gag synthesis by binding Rev and competing with it for CBP80, sequestering Rev in the cytoplasm.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, reporter assays, subcellular fractionation\",\n      \"pmids\": [\"33103564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"N-terminal Rev-binding interface not structurally defined\", \"In vivo relevance to viral replication not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TRIM28 as a negative regulator of CTIF-mediated aggresome formation downstream of PKR signaling, linking the CED pathway to antiviral defense.\",\n      \"evidence\": \"Co-IP, PLA, phosphomimetic mutants, aggresome and viral proliferation assays\",\n      \"pmids\": [\"33783327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM28 binding blocks CED assembly or transport not distinguished\", \"TRIM28-CTIF interface unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, reporter assays, confocal microscopy, polysome fractionation\",\n      \"pmids\": [\"34232997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Helicase-dependence of the handover step not biochemically dissected\", \"Structural basis of CTIF-DDX19B interaction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified YTHDF2 as an m6A-independent enhancer of aggresome targeting that strengthens dynein engagement of the CTIF-eEF1A1-DCTN1 complex via UPF1.\",\n      \"evidence\": \"Co-IP, live-cell imaging of aggresome dynamics, siRNA, apoptosis assay\",\n      \"pmids\": [\"37803021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CTIF studied as part of a pre-established complex, not the primary subject\", \"Direct YTHDF2-CTIF contact not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of CTIF itself\", \"Mechanism partitioning CTIF between translation and proteostasis pools unresolved\", \"Physiological/disease contexts of these activities not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 9, 11]}\n    ],\n    \"complexes\": [\n      \"CBP80/20-dependent translation initiation complex (CBC-CTIF)\",\n      \"CED complex (CTIF-eEF1A1-DCTN1)\"\n    ],\n    \"partners\": [\n      \"CBP80\",\n      \"EIF3G\",\n      \"EIF4A3\",\n      \"SLBP\",\n      \"DDX19B\",\n      \"EEF1A1\",\n      \"DCTN1\",\n      \"TRIM28\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}