{"gene":"GSPT1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2005,"finding":"eRF3a/GSPT1 (but not eRF3b) is the major translation termination factor in human cells: siRNA-mediated depletion of eRF3a caused a significant increase in readthrough at a premature nonsense codon, while eRF3b depletion had no significant effect. eRF3a depletion also reduced intracellular eRF1 protein levels by decreasing its stability, demonstrating that eRF3a controls formation of the translation termination complex by stabilizing eRF1.","method":"siRNA knockdown, reporter readthrough assay, western blot for eRF1 stability","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with specific functional readout (nonsense codon readthrough), two orthogonal methods (readthrough reporter + protein stability assay), single lab","pmids":["15987998"],"is_preprint":false},{"year":2007,"finding":"eRF3a/GSPT1 is degraded by the proteasome when not associated with eRF1. eRF3a mutants altered in the eRF1-binding site showed decreased stability that was rescued by the proteasome inhibitor MG132, and both mutant and wild-type eRF3a were found to be polyubiquitinated. This proteasomal degradation of free eRF3a adjusts eRF3a levels to match eRF1 levels, thereby controlling translation termination complex formation.","method":"Mutagenesis of eRF1-binding site, proteasome inhibitor (MG132) treatment, polyubiquitination assay, western blot","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of binding site combined with proteasome inhibition and ubiquitination assay, single lab, multiple orthogonal methods","pmids":["18083835"],"is_preprint":false},{"year":2003,"finding":"GSPT1/eRF3 is proteolytically processed into a shorter isoform that harbors a conserved N-terminal IAP-binding motif (AKPF). The processed isoform interacts biochemically with IAP proteins, promotes caspase activation, IAP ubiquitination, and apoptosis. The IAP-binding motif is absolutely required for these activities.","method":"Identification of processed isoform, biochemical pulldown/co-IP with IAPs, caspase activation assay, IAP ubiquitination assay, mutagenesis of IAP-binding motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of functional motif combined with biochemical interaction assays and functional caspase/apoptosis readouts, single lab, multiple orthogonal methods","pmids":["12865429"],"is_preprint":false},{"year":2016,"finding":"eRF3a/GSPT1 N-terminal glycine repeat influences binding affinity to PABP (cytoplasmic poly(A) binding protein) via two overlapping PAM2 motifs that recognize the MLLE domain of PABP. The cancer-associated 12-GGC allele (encoding 12 glycines) has decreased binding affinity for PABP compared to the common 10-GGC allele, as measured by surface plasmon resonance, suggesting that this allele could modify coupling between translation termination and mRNA deadenylation.","method":"Surface plasmon resonance (SPR) binding assay with allelic forms of eRF3a N-terminal domain and PABP or poly(A)-bound PABP","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — quantitative biophysical binding assay (SPR) with multiple alleles, but single lab and single method","pmids":["26818177"],"is_preprint":false},{"year":2002,"finding":"Mouse GSPT2 but not GSPT1 can functionally substitute for the essential yeast eRF3 gene SUP35 in vivo. The region spanning amino acids 84-120 of mGSPT1 prevents complementation of the sup35 mutation, but this region alone is insufficient to block complementation; the full-length mGSPT1 context is required. Complementation was achieved with mGSPT2 co-expressed with human eRF1 but not with mGSPT1 and human eRF1, indicating the two mammalian paralogs are functionally distinct.","method":"Yeast genetic complementation of SUP35 deletion, N-terminal deletion constructs, chimeric protein analysis","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis/complementation in yeast with multiple deletion and chimeric constructs, orthogonal approach, single lab","pmids":["12354098"],"is_preprint":false},{"year":2016,"finding":"A novel Rac1-GSPT1 signaling axis controls astrocyte proliferation in the context of inflammation and CNS injury. Rac1 knockout or knockdown in astrocytes decreased GSPT1 expression and reduced cell cycle progression; overexpression of GSPT1 rescued the cell cycle delay induced by Rac1 knockdown. GSPT1-KD astrocytes showed cell cycle delay but no effect on cell migration, placing GSPT1 downstream of Rac1 in the proliferation (but not migration) arm of astrogliosis signaling.","method":"Conditional Rac1 knockout mice (GFAP-Cre;Rac1flox/flox), siRNA knockdown, overexpression rescue, cell cycle analysis, in vivo spinal cord injury model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo combined with KD, rescue experiment by GSPT1 overexpression, and cell cycle readout; single lab but multiple orthogonal approaches","pmids":["27941025"],"is_preprint":false},{"year":2022,"finding":"GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response (ISR) pathway, and TP53-independent cell death in leukemia cells. CRISPR/Cas9 screens identified decreased translation initiation as protective following GSPT1 degradation, suggesting cells with higher translation rates are more susceptible. Two specific Crbn amino acids in mice prevent Gspt1 degradation by the molecular glue drugs, which was confirmed in a knockin mouse model that enabled in vivo efficacy studies while sparing hematopoietic stem cells.","method":"CRISPR/Cas9 screens, domain-mapping experiments, knockin mouse model, flow cytometry, western blot for ISR markers","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screens, domain-essential mutants, engineered knockin mouse, multiple orthogonal readouts, mechanistically defined pathway","pmids":["35763353"],"is_preprint":false},{"year":2022,"finding":"GSPT1/eRF3a physically associates with Lassa virus polymerase, identified by proximity proteomics (TurboID), and functions as a proviral host factor. siRNA knockdown of GSPT1 inhibited authentic LASV infection, and targeted degradation of GSPT1 by CC-90009 strongly inhibited LASV infection in cultured cells.","method":"Proximity proteomics (TurboID biotin ligase fusion), siRNA screen, small-molecule degrader treatment, plaque/infection assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics for interaction identification, functional siRNA and degrader validation, single lab","pmids":["35858434"],"is_preprint":false},{"year":2022,"finding":"eRF3a/GSPT1 degraders (cereblon E3 ligase modulators) rescue W1282X-CFTR premature termination codon function to ~20% of WT levels by promoting PTC readthrough; when paired with G418, they rescue G542X-CFTR function to ~50% of WT. eRF3a degraders also diminished epithelial sodium channel (ENaC) function.","method":"CFTR ion transport assays in airway epithelial cell lines, small-molecule eRF3a degrader treatment, Ussing chamber electrophysiology","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ion transport assays with mechanistic link to eRF3a degradation, single lab, two orthogonal cellular outputs","pmids":["35900863"],"is_preprint":false},{"year":2019,"finding":"eRF3A/GSPT1 depletion globally de-represses expression of mRNAs containing translated upstream open reading frames (uORFs) while having opposing effects on ribosome protein gene expression compared to UPF1 knockdown. Less than 250 transcripts were targeted by both eRF3A and UPF1, demonstrating that their roles in NMD are largely non-overlapping.","method":"RNA sequencing, ribosome profiling, siRNA knockdown of eRF3A and UPF1 in human cells","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ribosome profiling + RNA-seq with siRNA KD, two factors compared, single lab","pmids":["31619139"],"is_preprint":false},{"year":2018,"finding":"GSPT1 is recruited to the CRL4CRBN (CUL4-RBX1-DDB1-CRBN) E3 ubiquitin ligase by small-molecule phthalimide degraders, resulting in its ubiquitination and proteasomal degradation. This was identified as an off-target event independent of the targeting ligand in the bifunctional degrader molecules, confirmed by orthogonal target identification and molecular docking into the CRBN-GSPT1 interface.","method":"Quantitative chemical proteomics, molecular docking, cell viability assays in leukemia lines","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative chemical proteomics for target ID plus molecular docking, single lab","pmids":["29356495"],"is_preprint":false},{"year":2022,"finding":"GSPT1 degradation by cereblon modulator CC-885 is effective against glioblastoma in vivo. GSPT1-knockout U87 glioblastoma cells showed enhanced apoptosis (as measured by cleaved PARP1), and mice transplanted with GSPT1-KO cells had significantly longer survival than WT controls; rescue by re-expression of GSPT1 reversed the survival benefit, establishing that GSPT1 is essential for glioblastoma cell survival.","method":"GSPT1 CRISPR/Cas9 knockout, rescue overexpression, in vivo xenograft survival model, cleaved PARP1 apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with rescue experiment in vivo, apoptosis readout, single lab","pmids":["39117611"],"is_preprint":false},{"year":2021,"finding":"CC-90009 is a cereblon E3 ligase modulating drug that specifically targets GSPT1 for proteasomal degradation via the CRL4CRBN complex, representing the first CELMoD to enter clinical development for this mechanism in AML.","method":"Quantitative proteomics, cell-based degradation assays, pharmacokinetic characterization, in vivo efficacy models","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics for selectivity plus in vivo efficacy, single lab (industry), mechanism of action confirmed by proteasome pathway","pmids":["33591756"],"is_preprint":false},{"year":2014,"finding":"GSPT1 is induced by nicotine and EGF in an ID1-dependent manner in NSCLC cells. ID1 induces GSPT1 at the transcriptional level by downregulating two transcriptional co-repressors, NRSF and ZBP89. Depletion of GSPT1 abrogated nicotine-induced proliferation, invasion, and migration of NSCLC cells.","method":"Microarray, siRNA knockdown, overexpression, RT-PCR, invasion/migration assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA KD with functional readouts and mechanism for ID1-mediated induction, single lab, multiple cell lines","pmids":["25028095"],"is_preprint":false},{"year":2022,"finding":"eRF3a (GSPT1) overexpression promotes proliferation and migration of liver cancer cells through activation of the ERK and JNK signaling pathways, as determined by western blot analysis of pathway markers upon eRF3a overexpression.","method":"Overexpression in liver cancer cell lines, CCK8, colony formation, Transwell assay, western blot for ERK/JNK pathway markers","journal":"Current medical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach, pathway attribution based on western blot without pathway-specific rescue","pmids":["34985612"],"is_preprint":false},{"year":2025,"finding":"GSPT1 senses the stop codon of MYC mRNA to promote MYC translation, and MYC in turn promotes transcription of GSPT1, establishing a co-regulatory positive feedback loop. Dual MYC/GSPT1 protein degradation by GT19630 activates the integrated stress response, abrogates oxidative phosphorylation via inhibition of the TCA cycle, and induces TP53-independent cell death.","method":"Reporter assays for MYC translation, transcriptional analysis, dual degrader treatment, ISR marker analysis, metabolomics (TCA cycle), xenograft models","journal":"bioRxiv (PREPRINT)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, novel regulatory loop claim not yet peer-reviewed, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"GSPT1 loss reduces translation efficiency particularly for proteins with short half-lives such as c-Myc. GSPT1 degradation in IRAK4-inhibited leukemic cells leads to accelerated c-Myc protein loss due to decreased protein stability, providing a mechanistic basis for synergy between IRAK4 inhibitors and GSPT1-targeting CELMoDs.","method":"Transcriptional and proteomic analyses, western blot for c-Myc protein stability, AML cell lines, primary patient samples","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional protein stability assays across multiple cell contexts, mechanistic pathway defined, single lab","pmids":["40670672"],"is_preprint":false},{"year":2025,"finding":"GSPT1 degradation impairs expression of leukemic fusion gene transcripts (RUNX1::RUNX1T1 and FUS::ERG) and their cooperating transcription factors RUNX1 and ERG in pediatric AML cells, revealing a novel role for GSPT1 in regulating leukemic transcriptional networks.","method":"CC-90009 and CDK6-PROTAC (GU3341) treatment, western blot, RT-PCR for fusion transcripts, in vitro and ex vivo AML cell experiments","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological degradation without genetic rescue to confirm specificity of the transcriptional effect","pmids":["39857993"],"is_preprint":false},{"year":2025,"finding":"GSPT1 promotes Parkin ubiquitination and is associated with altered Parkin turnover under mitochondrial stress, thereby enhancing compensatory mitophagy in lung adenocarcinoma cells. GSPT1 overexpression reversed the inhibitory effects of TMEM106C silencing on cancer growth and restored mitophagy.","method":"RNA immunoprecipitation, cycloheximide chase, GFP-mRFP-LC3 mitophagy assay, transmission electron microscopy, western blot for autophagy markers, xenograft model","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional rescue approach for the GSPT1-Parkin link but mechanistic detail of how GSPT1 promotes Parkin ubiquitination is indirect","pmids":["42167422"],"is_preprint":false},{"year":2025,"finding":"CC-90009-mediated degradation of GSPT1 inhibits Japanese encephalitis virus (JEV) infection by disrupting viral translation and replication. Co-immunoprecipitation confirmed that GSPT1 physically interacts with the JEV non-structural protein NS5, and CC-90009 induces proteasomal degradation of the GSPT1/NS5 complex.","method":"Co-immunoprecipitation, siRNA knockdown of GSPT1, CC-90009 treatment, JEV infection assay, viral RNA and protein quantification, in vivo murine JEV model","journal":"Pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, siRNA knockdown confirming proviral role, degrader treatment, in vivo validation, single lab","pmids":["41471039"],"is_preprint":false}],"current_model":"GSPT1 (eRF3a) is a GTPase translation termination factor that forms a complex with eRF1 to mediate stop codon recognition; free (eRF1-unbound) GSPT1 is polyubiquitinated and degraded by the proteasome to maintain stoichiometry of the termination complex, while GSPT1 association with PABP via PAM2 motifs couples termination to mRNA deadenylation, and GSPT1 can be proteolytically processed into an IAP-binding pro-apoptotic isoform; additionally, GSPT1 functions downstream of Rac1 to promote astrocyte proliferation, acts as a proviral host factor by physically interacting with viral polymerases, and is selectively recruited to the CRL4CRBN E3 ubiquitin ligase by molecular glue compounds (CELMoDs) such as CC-90009, leading to its proteasomal degradation, impaired translation termination, integrated stress response activation, and TP53-independent cancer cell death."},"narrative":{"mechanistic_narrative":"GSPT1 (eRF3a) is the major translation termination factor in human cells, functioning as a GTPase that partners with eRF1 to mediate stop codon recognition; depletion of eRF3a increases nonsense codon readthrough and destabilizes eRF1, establishing that eRF3a controls assembly of the termination complex by stabilizing its partner [PMID:15987998]. Stoichiometry between the two factors is enforced by proteasomal quality control: eRF3a that is not bound to eRF1 is polyubiquitinated and degraded, so free eRF3a levels are adjusted to match eRF1 [PMID:18083835]. Beyond canonical termination, eRF3a couples termination to mRNA fate through two overlapping PAM2 motifs that engage the MLLE domain of cytoplasmic PABP, with allelic glycine-repeat variation tuning this binding affinity [PMID:26818177], and its loss globally de-represses uORF-containing mRNAs through an NMD role largely non-overlapping with UPF1 [PMID:31619139]. GSPT1 is proteolytically processed into a shorter isoform bearing an N-terminal IAP-binding motif that engages IAP proteins, promotes IAP ubiquitination and caspase activation, and drives apoptosis [PMID:12865429]. GSPT1 also acts in cell proliferation, functioning downstream of Rac1 to drive astrocyte cell-cycle progression [PMID:27941025]. Therapeutically, GSPT1 is recruited to the CRL4CRBN E3 ubiquitin ligase by cereblon-modulating molecular-glue compounds (CC-90009 and related CELMoDs), leading to its ubiquitination and proteasomal degradation, impaired translation termination, integrated stress response activation, and TP53-independent cancer cell death in leukemia and glioblastoma [PMID:35763353, PMID:29356495, PMID:39117611, PMID:33591756]. GSPT1 additionally serves as a proviral host factor, physically associating with viral polymerases including Lassa virus polymerase and JEV NS5, such that its degradation suppresses viral infection [PMID:35858434, PMID:41471039].","teleology":[{"year":2002,"claim":"Established that the two mammalian eRF3 paralogs are functionally distinct, framing GSPT1/eRF3a as a non-interchangeable termination factor.","evidence":"Yeast SUP35 complementation with chimeric and deletion constructs of mouse GSPT1/GSPT2 plus human eRF1","pmids":["12354098"],"confidence":"High","gaps":["Does not define the human cellular role of eRF3a versus eRF3b directly","The functional consequence of the GSPT1 84-120 region in mammalian cells is unresolved"]},{"year":2003,"claim":"Revealed a non-termination role: proteolytically processed GSPT1 acts as a pro-apoptotic IAP antagonist, answering whether eRF3 had functions beyond translation.","evidence":"Identification of processed isoform, IAP co-IP, caspase/IAP-ubiquitination assays, and IAP-binding motif mutagenesis","pmids":["12865429"],"confidence":"High","gaps":["Protease and physiological trigger for processing not identified","In vivo relevance of the apoptotic isoform unestablished"]},{"year":2005,"claim":"Demonstrated that eRF3a, not eRF3b, is the major termination factor and stabilizes eRF1, defining the core mechanism of termination complex formation.","evidence":"siRNA depletion with nonsense codon readthrough reporter and eRF1 protein stability western blots","pmids":["15987998"],"confidence":"High","gaps":["Structural basis of eRF1 stabilization not resolved","Does not address GTPase catalytic cycle directly"]},{"year":2007,"claim":"Explained how eRF3a/eRF1 stoichiometry is maintained: free eRF3a is polyubiquitinated and degraded, coupling complex assembly to protein turnover.","evidence":"eRF1-binding-site mutagenesis, MG132 proteasome inhibition, and polyubiquitination assays","pmids":["18083835"],"confidence":"High","gaps":["E3 ligase responsible for free eRF3a degradation not identified","Cellular signals tuning this balance unknown"]},{"year":2014,"claim":"Linked GSPT1 to oncogenic signaling by showing it is a transcriptional effector of nicotine/EGF-ID1 signaling driving NSCLC proliferation and invasion.","evidence":"Microarray, siRNA knockdown, overexpression, and invasion/migration assays in NSCLC cells","pmids":["25028095"],"confidence":"Medium","gaps":["Mechanism connecting GSPT1 termination activity to proliferation not defined","Direct ID1-GSPT1 promoter regulation indirectly inferred via co-repressor downregulation"]},{"year":2016,"claim":"Quantified how GSPT1 couples termination to deadenylation by mapping PAM2-MLLE binding and showing a cancer-associated allele alters PABP affinity.","evidence":"Surface plasmon resonance with allelic eRF3a N-terminal domains against PABP","pmids":["26818177"],"confidence":"Medium","gaps":["Functional impact on deadenylation/translation in cells not shown","Single biophysical method"]},{"year":2016,"claim":"Placed GSPT1 downstream of Rac1 in a proliferation-specific signaling axis controlling astrocyte cell-cycle progression.","evidence":"Conditional Rac1 knockout mice, siRNA knockdown, GSPT1 overexpression rescue, and cell cycle/spinal cord injury models","pmids":["27941025"],"confidence":"High","gaps":["Molecular link from Rac1 to GSPT1 expression unresolved","Whether the effect requires termination activity is unknown"]},{"year":2018,"claim":"Identified GSPT1 as a cereblon neosubstrate, showing molecular-glue degraders recruit it to CRL4CRBN for proteasomal degradation.","evidence":"Quantitative chemical proteomics, molecular docking into the CRBN-GSPT1 interface, and leukemia viability assays","pmids":["29356495"],"confidence":"Medium","gaps":["Initially an off-target finding; selectivity over other neosubstrates not fully defined here","No high-resolution structure of the ternary complex"]},{"year":2019,"claim":"Defined the global mRNA consequences of GSPT1 loss, showing de-repression of uORF-containing transcripts and an NMD role largely distinct from UPF1.","evidence":"RNA-seq and ribosome profiling after siRNA knockdown of eRF3A versus UPF1","pmids":["31619139"],"confidence":"Medium","gaps":["Mechanism of uORF-specific regulation not resolved","Overlap with other termination/NMD factors not mapped"]},{"year":2021,"claim":"Advanced GSPT1 degradation to a clinical-stage strategy by characterizing CC-90009 as a selective CRL4CRBN-mediated GSPT1 degrader for AML.","evidence":"Quantitative proteomics, cell degradation assays, pharmacokinetics, and in vivo efficacy models","pmids":["33591756"],"confidence":"Medium","gaps":["Downstream death pathway not fully dissected in this report","Resistance mechanisms not addressed"]},{"year":2022,"claim":"Mechanistically connected GSPT1 degradation to impaired termination, ISR activation, and TP53-independent leukemic death, and engineered a Crbn knockin sparing hematopoietic stem cells for in vivo study.","evidence":"Genome-wide CRISPR screens, Crbn domain-mapping, knockin mouse model, and ISR marker readouts","pmids":["35763353"],"confidence":"High","gaps":["Precise trigger linking termination defect to ISR not fully defined","Why high translation rate sensitizes cells remains mechanistically open"]},{"year":2022,"claim":"Extended therapeutic logic to nonsense-mutation diseases, showing eRF3a degraders promote CFTR premature-termination-codon readthrough.","evidence":"CFTR ion transport and Ussing chamber assays in airway epithelial cells with eRF3a degraders, alone and with G418","pmids":["35900863"],"confidence":"Medium","gaps":["ENaC off-effect could limit therapeutic window","Readthrough efficiency remains submaximal"]},{"year":2022,"claim":"Established GSPT1 as a proviral host factor by showing physical association with Lassa virus polymerase and antiviral effect of its degradation.","evidence":"TurboID proximity proteomics, siRNA screen, and CC-90009 degrader treatment in LASV infection assays","pmids":["35858434"],"confidence":"Medium","gaps":["Direct binding versus proximity not distinguished","Mechanism of polymerase support undefined"]},{"year":2022,"claim":"Demonstrated GSPT1 is essential for glioblastoma survival and a degradation target in that tumor type.","evidence":"CRISPR knockout with rescue, in vivo xenograft survival, and cleaved-PARP1 apoptosis assays with CC-885","pmids":["39117611"],"confidence":"Medium","gaps":["Whether dependence reflects termination activity specifically is unclear","ISR involvement in GBM not directly tested"]},{"year":2025,"claim":"Provided a mechanistic basis for combination therapy by showing GSPT1 loss preferentially reduces translation of short-half-life proteins like c-Myc, synergizing with IRAK4 inhibition.","evidence":"Proteomics and c-Myc protein stability western blots in AML cell lines and primary samples","pmids":["40670672"],"confidence":"Medium","gaps":["Generalizability beyond c-Myc not fully mapped","Quantitative contribution of termination versus initiation effects unresolved"]},{"year":2025,"claim":"Implicated GSPT1 degradation in disrupting leukemic fusion-driven transcriptional networks in pediatric AML.","evidence":"CC-90009 and CDK6-PROTAC treatment with western blot and RT-PCR for fusion transcripts in AML cells","pmids":["39857993"],"confidence":"Low","gaps":["Pharmacological degradation without genetic rescue to confirm specificity","Direct versus indirect effect on fusion transcription not separated"]},{"year":2025,"claim":"Proposed mitochondrial-quality-control involvement, linking GSPT1 to Parkin ubiquitination and compensatory mitophagy in lung adenocarcinoma.","evidence":"RNA immunoprecipitation, cycloheximide chase, LC3 mitophagy reporter, electron microscopy, and xenograft rescue of TMEM106C silencing","pmids":["42167422"],"confidence":"Low","gaps":["Mechanism by which GSPT1 promotes Parkin ubiquitination is indirect","Not independently confirmed"]},{"year":2025,"claim":"Extended antiviral degrader strategy to flaviviruses, showing GSPT1 interacts with JEV NS5 and its CC-90009-mediated degradation suppresses infection.","evidence":"Co-immunoprecipitation, siRNA knockdown, CC-90009 treatment, and an in vivo murine JEV model","pmids":["41471039"],"confidence":"Medium","gaps":["Direct binding interface with NS5 not mapped","Role in viral translation versus replication not fully separated"]},{"year":null,"claim":"How GSPT1 degradation mechanistically triggers the integrated stress response and selectively kills cancer cells, and whether its non-termination roles (apoptosis, proliferation signaling, mitophagy) depend on its termination activity, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Causal link from termination defect to ISR/eIF2alpha signaling not defined","Structural model of the CRBN-GSPT1 ternary complex not in corpus","Integration of GTPase, apoptotic, and signaling functions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,11]}],"complexes":["eRF1-eRF3a translation termination complex","CRL4CRBN E3 ubiquitin ligase (neosubstrate)"],"partners":["ETF1","PABPC1","CRBN","BIRC2","RAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15170","full_name":"Eukaryotic peptide chain release factor GTP-binding subunit ERF3A","aliases":["G1 to S phase transition protein 1 homolog"],"length_aa":499,"mass_kda":55.8,"function":"GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA (PubMed:15987998, PubMed:19417105, PubMed:2511002, PubMed:27863242). GSPT1/ERF3A mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site (PubMed:27863242). GTP hydrolysis by GSPT1/ERF3A induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site (PubMed:16777602, PubMed:27863242). Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:24486019). Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes (PubMed:30682371)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P15170/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GSPT1","classification":"Common 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stability, demonstrating that eRF3a controls formation of the translation termination complex by stabilizing eRF1.\",\n      \"method\": \"siRNA knockdown, reporter readthrough assay, western blot for eRF1 stability\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD with specific functional readout (nonsense codon readthrough), two orthogonal methods (readthrough reporter + protein stability assay), single lab\",\n      \"pmids\": [\"15987998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"eRF3a/GSPT1 is degraded by the proteasome when not associated with eRF1. eRF3a mutants altered in the eRF1-binding site showed decreased stability that was rescued by the proteasome inhibitor MG132, and both mutant and wild-type eRF3a were found to be polyubiquitinated. This proteasomal degradation of free eRF3a adjusts eRF3a levels to match eRF1 levels, thereby controlling translation termination complex formation.\",\n      \"method\": \"Mutagenesis of eRF1-binding site, proteasome inhibitor (MG132) treatment, polyubiquitination assay, western blot\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of binding site combined with proteasome inhibition and ubiquitination assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18083835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GSPT1/eRF3 is proteolytically processed into a shorter isoform that harbors a conserved N-terminal IAP-binding motif (AKPF). The processed isoform interacts biochemically with IAP proteins, promotes caspase activation, IAP ubiquitination, and apoptosis. The IAP-binding motif is absolutely required for these activities.\",\n      \"method\": \"Identification of processed isoform, biochemical pulldown/co-IP with IAPs, caspase activation assay, IAP ubiquitination assay, mutagenesis of IAP-binding motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of functional motif combined with biochemical interaction assays and functional caspase/apoptosis readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12865429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"eRF3a/GSPT1 N-terminal glycine repeat influences binding affinity to PABP (cytoplasmic poly(A) binding protein) via two overlapping PAM2 motifs that recognize the MLLE domain of PABP. The cancer-associated 12-GGC allele (encoding 12 glycines) has decreased binding affinity for PABP compared to the common 10-GGC allele, as measured by surface plasmon resonance, suggesting that this allele could modify coupling between translation termination and mRNA deadenylation.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding assay with allelic forms of eRF3a N-terminal domain and PABP or poly(A)-bound PABP\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — quantitative biophysical binding assay (SPR) with multiple alleles, but single lab and single method\",\n      \"pmids\": [\"26818177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse GSPT2 but not GSPT1 can functionally substitute for the essential yeast eRF3 gene SUP35 in vivo. The region spanning amino acids 84-120 of mGSPT1 prevents complementation of the sup35 mutation, but this region alone is insufficient to block complementation; the full-length mGSPT1 context is required. Complementation was achieved with mGSPT2 co-expressed with human eRF1 but not with mGSPT1 and human eRF1, indicating the two mammalian paralogs are functionally distinct.\",\n      \"method\": \"Yeast genetic complementation of SUP35 deletion, N-terminal deletion constructs, chimeric protein analysis\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis/complementation in yeast with multiple deletion and chimeric constructs, orthogonal approach, single lab\",\n      \"pmids\": [\"12354098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A novel Rac1-GSPT1 signaling axis controls astrocyte proliferation in the context of inflammation and CNS injury. Rac1 knockout or knockdown in astrocytes decreased GSPT1 expression and reduced cell cycle progression; overexpression of GSPT1 rescued the cell cycle delay induced by Rac1 knockdown. GSPT1-KD astrocytes showed cell cycle delay but no effect on cell migration, placing GSPT1 downstream of Rac1 in the proliferation (but not migration) arm of astrogliosis signaling.\",\n      \"method\": \"Conditional Rac1 knockout mice (GFAP-Cre;Rac1flox/flox), siRNA knockdown, overexpression rescue, cell cycle analysis, in vivo spinal cord injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo combined with KD, rescue experiment by GSPT1 overexpression, and cell cycle readout; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"27941025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response (ISR) pathway, and TP53-independent cell death in leukemia cells. CRISPR/Cas9 screens identified decreased translation initiation as protective following GSPT1 degradation, suggesting cells with higher translation rates are more susceptible. Two specific Crbn amino acids in mice prevent Gspt1 degradation by the molecular glue drugs, which was confirmed in a knockin mouse model that enabled in vivo efficacy studies while sparing hematopoietic stem cells.\",\n      \"method\": \"CRISPR/Cas9 screens, domain-mapping experiments, knockin mouse model, flow cytometry, western blot for ISR markers\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screens, domain-essential mutants, engineered knockin mouse, multiple orthogonal readouts, mechanistically defined pathway\",\n      \"pmids\": [\"35763353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSPT1/eRF3a physically associates with Lassa virus polymerase, identified by proximity proteomics (TurboID), and functions as a proviral host factor. siRNA knockdown of GSPT1 inhibited authentic LASV infection, and targeted degradation of GSPT1 by CC-90009 strongly inhibited LASV infection in cultured cells.\",\n      \"method\": \"Proximity proteomics (TurboID biotin ligase fusion), siRNA screen, small-molecule degrader treatment, plaque/infection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics for interaction identification, functional siRNA and degrader validation, single lab\",\n      \"pmids\": [\"35858434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eRF3a/GSPT1 degraders (cereblon E3 ligase modulators) rescue W1282X-CFTR premature termination codon function to ~20% of WT levels by promoting PTC readthrough; when paired with G418, they rescue G542X-CFTR function to ~50% of WT. eRF3a degraders also diminished epithelial sodium channel (ENaC) function.\",\n      \"method\": \"CFTR ion transport assays in airway epithelial cell lines, small-molecule eRF3a degrader treatment, Ussing chamber electrophysiology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ion transport assays with mechanistic link to eRF3a degradation, single lab, two orthogonal cellular outputs\",\n      \"pmids\": [\"35900863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"eRF3A/GSPT1 depletion globally de-represses expression of mRNAs containing translated upstream open reading frames (uORFs) while having opposing effects on ribosome protein gene expression compared to UPF1 knockdown. Less than 250 transcripts were targeted by both eRF3A and UPF1, demonstrating that their roles in NMD are largely non-overlapping.\",\n      \"method\": \"RNA sequencing, ribosome profiling, siRNA knockdown of eRF3A and UPF1 in human cells\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ribosome profiling + RNA-seq with siRNA KD, two factors compared, single lab\",\n      \"pmids\": [\"31619139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GSPT1 is recruited to the CRL4CRBN (CUL4-RBX1-DDB1-CRBN) E3 ubiquitin ligase by small-molecule phthalimide degraders, resulting in its ubiquitination and proteasomal degradation. This was identified as an off-target event independent of the targeting ligand in the bifunctional degrader molecules, confirmed by orthogonal target identification and molecular docking into the CRBN-GSPT1 interface.\",\n      \"method\": \"Quantitative chemical proteomics, molecular docking, cell viability assays in leukemia lines\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative chemical proteomics for target ID plus molecular docking, single lab\",\n      \"pmids\": [\"29356495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSPT1 degradation by cereblon modulator CC-885 is effective against glioblastoma in vivo. GSPT1-knockout U87 glioblastoma cells showed enhanced apoptosis (as measured by cleaved PARP1), and mice transplanted with GSPT1-KO cells had significantly longer survival than WT controls; rescue by re-expression of GSPT1 reversed the survival benefit, establishing that GSPT1 is essential for glioblastoma cell survival.\",\n      \"method\": \"GSPT1 CRISPR/Cas9 knockout, rescue overexpression, in vivo xenograft survival model, cleaved PARP1 apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with rescue experiment in vivo, apoptosis readout, single lab\",\n      \"pmids\": [\"39117611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CC-90009 is a cereblon E3 ligase modulating drug that specifically targets GSPT1 for proteasomal degradation via the CRL4CRBN complex, representing the first CELMoD to enter clinical development for this mechanism in AML.\",\n      \"method\": \"Quantitative proteomics, cell-based degradation assays, pharmacokinetic characterization, in vivo efficacy models\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics for selectivity plus in vivo efficacy, single lab (industry), mechanism of action confirmed by proteasome pathway\",\n      \"pmids\": [\"33591756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GSPT1 is induced by nicotine and EGF in an ID1-dependent manner in NSCLC cells. ID1 induces GSPT1 at the transcriptional level by downregulating two transcriptional co-repressors, NRSF and ZBP89. Depletion of GSPT1 abrogated nicotine-induced proliferation, invasion, and migration of NSCLC cells.\",\n      \"method\": \"Microarray, siRNA knockdown, overexpression, RT-PCR, invasion/migration assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA KD with functional readouts and mechanism for ID1-mediated induction, single lab, multiple cell lines\",\n      \"pmids\": [\"25028095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eRF3a (GSPT1) overexpression promotes proliferation and migration of liver cancer cells through activation of the ERK and JNK signaling pathways, as determined by western blot analysis of pathway markers upon eRF3a overexpression.\",\n      \"method\": \"Overexpression in liver cancer cell lines, CCK8, colony formation, Transwell assay, western blot for ERK/JNK pathway markers\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach, pathway attribution based on western blot without pathway-specific rescue\",\n      \"pmids\": [\"34985612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GSPT1 senses the stop codon of MYC mRNA to promote MYC translation, and MYC in turn promotes transcription of GSPT1, establishing a co-regulatory positive feedback loop. Dual MYC/GSPT1 protein degradation by GT19630 activates the integrated stress response, abrogates oxidative phosphorylation via inhibition of the TCA cycle, and induces TP53-independent cell death.\",\n      \"method\": \"Reporter assays for MYC translation, transcriptional analysis, dual degrader treatment, ISR marker analysis, metabolomics (TCA cycle), xenograft models\",\n      \"journal\": \"bioRxiv (PREPRINT)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, novel regulatory loop claim not yet peer-reviewed, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GSPT1 loss reduces translation efficiency particularly for proteins with short half-lives such as c-Myc. GSPT1 degradation in IRAK4-inhibited leukemic cells leads to accelerated c-Myc protein loss due to decreased protein stability, providing a mechanistic basis for synergy between IRAK4 inhibitors and GSPT1-targeting CELMoDs.\",\n      \"method\": \"Transcriptional and proteomic analyses, western blot for c-Myc protein stability, AML cell lines, primary patient samples\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional protein stability assays across multiple cell contexts, mechanistic pathway defined, single lab\",\n      \"pmids\": [\"40670672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GSPT1 degradation impairs expression of leukemic fusion gene transcripts (RUNX1::RUNX1T1 and FUS::ERG) and their cooperating transcription factors RUNX1 and ERG in pediatric AML cells, revealing a novel role for GSPT1 in regulating leukemic transcriptional networks.\",\n      \"method\": \"CC-90009 and CDK6-PROTAC (GU3341) treatment, western blot, RT-PCR for fusion transcripts, in vitro and ex vivo AML cell experiments\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological degradation without genetic rescue to confirm specificity of the transcriptional effect\",\n      \"pmids\": [\"39857993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GSPT1 promotes Parkin ubiquitination and is associated with altered Parkin turnover under mitochondrial stress, thereby enhancing compensatory mitophagy in lung adenocarcinoma cells. GSPT1 overexpression reversed the inhibitory effects of TMEM106C silencing on cancer growth and restored mitophagy.\",\n      \"method\": \"RNA immunoprecipitation, cycloheximide chase, GFP-mRFP-LC3 mitophagy assay, transmission electron microscopy, western blot for autophagy markers, xenograft model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional rescue approach for the GSPT1-Parkin link but mechanistic detail of how GSPT1 promotes Parkin ubiquitination is indirect\",\n      \"pmids\": [\"42167422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CC-90009-mediated degradation of GSPT1 inhibits Japanese encephalitis virus (JEV) infection by disrupting viral translation and replication. Co-immunoprecipitation confirmed that GSPT1 physically interacts with the JEV non-structural protein NS5, and CC-90009 induces proteasomal degradation of the GSPT1/NS5 complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of GSPT1, CC-90009 treatment, JEV infection assay, viral RNA and protein quantification, in vivo murine JEV model\",\n      \"journal\": \"Pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, siRNA knockdown confirming proviral role, degrader treatment, in vivo validation, single lab\",\n      \"pmids\": [\"41471039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GSPT1 (eRF3a) is a GTPase translation termination factor that forms a complex with eRF1 to mediate stop codon recognition; free (eRF1-unbound) GSPT1 is polyubiquitinated and degraded by the proteasome to maintain stoichiometry of the termination complex, while GSPT1 association with PABP via PAM2 motifs couples termination to mRNA deadenylation, and GSPT1 can be proteolytically processed into an IAP-binding pro-apoptotic isoform; additionally, GSPT1 functions downstream of Rac1 to promote astrocyte proliferation, acts as a proviral host factor by physically interacting with viral polymerases, and is selectively recruited to the CRL4CRBN E3 ubiquitin ligase by molecular glue compounds (CELMoDs) such as CC-90009, leading to its proteasomal degradation, impaired translation termination, integrated stress response activation, and TP53-independent cancer cell death.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GSPT1 (eRF3a) is the major translation termination factor in human cells, functioning as a GTPase that partners with eRF1 to mediate stop codon recognition; depletion of eRF3a increases nonsense codon readthrough and destabilizes eRF1, establishing that eRF3a controls assembly of the termination complex by stabilizing its partner [#0]. Stoichiometry between the two factors is enforced by proteasomal quality control: eRF3a that is not bound to eRF1 is polyubiquitinated and degraded, so free eRF3a levels are adjusted to match eRF1 [#1]. Beyond canonical termination, eRF3a couples termination to mRNA fate through two overlapping PAM2 motifs that engage the MLLE domain of cytoplasmic PABP, with allelic glycine-repeat variation tuning this binding affinity [#3], and its loss globally de-represses uORF-containing mRNAs through an NMD role largely non-overlapping with UPF1 [#9]. GSPT1 is proteolytically processed into a shorter isoform bearing an N-terminal IAP-binding motif that engages IAP proteins, promotes IAP ubiquitination and caspase activation, and drives apoptosis [#2]. GSPT1 also acts in cell proliferation, functioning downstream of Rac1 to drive astrocyte cell-cycle progression [#5]. Therapeutically, GSPT1 is recruited to the CRL4CRBN E3 ubiquitin ligase by cereblon-modulating molecular-glue compounds (CC-90009 and related CELMoDs), leading to its ubiquitination and proteasomal degradation, impaired translation termination, integrated stress response activation, and TP53-independent cancer cell death in leukemia and glioblastoma [#6, #10, #11, #12]. GSPT1 additionally serves as a proviral host factor, physically associating with viral polymerases including Lassa virus polymerase and JEV NS5, such that its degradation suppresses viral infection [#7, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that the two mammalian eRF3 paralogs are functionally distinct, framing GSPT1/eRF3a as a non-interchangeable termination factor.\",\n      \"evidence\": \"Yeast SUP35 complementation with chimeric and deletion constructs of mouse GSPT1/GSPT2 plus human eRF1\",\n      \"pmids\": [\"12354098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the human cellular role of eRF3a versus eRF3b directly\", \"The functional consequence of the GSPT1 84-120 region in mammalian cells is unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed a non-termination role: proteolytically processed GSPT1 acts as a pro-apoptotic IAP antagonist, answering whether eRF3 had functions beyond translation.\",\n      \"evidence\": \"Identification of processed isoform, IAP co-IP, caspase/IAP-ubiquitination assays, and IAP-binding motif mutagenesis\",\n      \"pmids\": [\"12865429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease and physiological trigger for processing not identified\", \"In vivo relevance of the apoptotic isoform unestablished\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that eRF3a, not eRF3b, is the major termination factor and stabilizes eRF1, defining the core mechanism of termination complex formation.\",\n      \"evidence\": \"siRNA depletion with nonsense codon readthrough reporter and eRF1 protein stability western blots\",\n      \"pmids\": [\"15987998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of eRF1 stabilization not resolved\", \"Does not address GTPase catalytic cycle directly\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Explained how eRF3a/eRF1 stoichiometry is maintained: free eRF3a is polyubiquitinated and degraded, coupling complex assembly to protein turnover.\",\n      \"evidence\": \"eRF1-binding-site mutagenesis, MG132 proteasome inhibition, and polyubiquitination assays\",\n      \"pmids\": [\"18083835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for free eRF3a degradation not identified\", \"Cellular signals tuning this balance unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked GSPT1 to oncogenic signaling by showing it is a transcriptional effector of nicotine/EGF-ID1 signaling driving NSCLC proliferation and invasion.\",\n      \"evidence\": \"Microarray, siRNA knockdown, overexpression, and invasion/migration assays in NSCLC cells\",\n      \"pmids\": [\"25028095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting GSPT1 termination activity to proliferation not defined\", \"Direct ID1-GSPT1 promoter regulation indirectly inferred via co-repressor downregulation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Quantified how GSPT1 couples termination to deadenylation by mapping PAM2-MLLE binding and showing a cancer-associated allele alters PABP affinity.\",\n      \"evidence\": \"Surface plasmon resonance with allelic eRF3a N-terminal domains against PABP\",\n      \"pmids\": [\"26818177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact on deadenylation/translation in cells not shown\", \"Single biophysical method\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed GSPT1 downstream of Rac1 in a proliferation-specific signaling axis controlling astrocyte cell-cycle progression.\",\n      \"evidence\": \"Conditional Rac1 knockout mice, siRNA knockdown, GSPT1 overexpression rescue, and cell cycle/spinal cord injury models\",\n      \"pmids\": [\"27941025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from Rac1 to GSPT1 expression unresolved\", \"Whether the effect requires termination activity is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified GSPT1 as a cereblon neosubstrate, showing molecular-glue degraders recruit it to CRL4CRBN for proteasomal degradation.\",\n      \"evidence\": \"Quantitative chemical proteomics, molecular docking into the CRBN-GSPT1 interface, and leukemia viability assays\",\n      \"pmids\": [\"29356495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Initially an off-target finding; selectivity over other neosubstrates not fully defined here\", \"No high-resolution structure of the ternary complex\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the global mRNA consequences of GSPT1 loss, showing de-repression of uORF-containing transcripts and an NMD role largely distinct from UPF1.\",\n      \"evidence\": \"RNA-seq and ribosome profiling after siRNA knockdown of eRF3A versus UPF1\",\n      \"pmids\": [\"31619139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of uORF-specific regulation not resolved\", \"Overlap with other termination/NMD factors not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Advanced GSPT1 degradation to a clinical-stage strategy by characterizing CC-90009 as a selective CRL4CRBN-mediated GSPT1 degrader for AML.\",\n      \"evidence\": \"Quantitative proteomics, cell degradation assays, pharmacokinetics, and in vivo efficacy models\",\n      \"pmids\": [\"33591756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream death pathway not fully dissected in this report\", \"Resistance mechanisms not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically connected GSPT1 degradation to impaired termination, ISR activation, and TP53-independent leukemic death, and engineered a Crbn knockin sparing hematopoietic stem cells for in vivo study.\",\n      \"evidence\": \"Genome-wide CRISPR screens, Crbn domain-mapping, knockin mouse model, and ISR marker readouts\",\n      \"pmids\": [\"35763353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise trigger linking termination defect to ISR not fully defined\", \"Why high translation rate sensitizes cells remains mechanistically open\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended therapeutic logic to nonsense-mutation diseases, showing eRF3a degraders promote CFTR premature-termination-codon readthrough.\",\n      \"evidence\": \"CFTR ion transport and Ussing chamber assays in airway epithelial cells with eRF3a degraders, alone and with G418\",\n      \"pmids\": [\"35900863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ENaC off-effect could limit therapeutic window\", \"Readthrough efficiency remains submaximal\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established GSPT1 as a proviral host factor by showing physical association with Lassa virus polymerase and antiviral effect of its degradation.\",\n      \"evidence\": \"TurboID proximity proteomics, siRNA screen, and CC-90009 degrader treatment in LASV infection assays\",\n      \"pmids\": [\"35858434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding versus proximity not distinguished\", \"Mechanism of polymerase support undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated GSPT1 is essential for glioblastoma survival and a degradation target in that tumor type.\",\n      \"evidence\": \"CRISPR knockout with rescue, in vivo xenograft survival, and cleaved-PARP1 apoptosis assays with CC-885\",\n      \"pmids\": [\"39117611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether dependence reflects termination activity specifically is unclear\", \"ISR involvement in GBM not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a mechanistic basis for combination therapy by showing GSPT1 loss preferentially reduces translation of short-half-life proteins like c-Myc, synergizing with IRAK4 inhibition.\",\n      \"evidence\": \"Proteomics and c-Myc protein stability western blots in AML cell lines and primary samples\",\n      \"pmids\": [\"40670672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond c-Myc not fully mapped\", \"Quantitative contribution of termination versus initiation effects unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated GSPT1 degradation in disrupting leukemic fusion-driven transcriptional networks in pediatric AML.\",\n      \"evidence\": \"CC-90009 and CDK6-PROTAC treatment with western blot and RT-PCR for fusion transcripts in AML cells\",\n      \"pmids\": [\"39857993\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacological degradation without genetic rescue to confirm specificity\", \"Direct versus indirect effect on fusion transcription not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed mitochondrial-quality-control involvement, linking GSPT1 to Parkin ubiquitination and compensatory mitophagy in lung adenocarcinoma.\",\n      \"evidence\": \"RNA immunoprecipitation, cycloheximide chase, LC3 mitophagy reporter, electron microscopy, and xenograft rescue of TMEM106C silencing\",\n      \"pmids\": [\"42167422\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism by which GSPT1 promotes Parkin ubiquitination is indirect\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended antiviral degrader strategy to flaviviruses, showing GSPT1 interacts with JEV NS5 and its CC-90009-mediated degradation suppresses infection.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, CC-90009 treatment, and an in vivo murine JEV model\",\n      \"pmids\": [\"41471039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface with NS5 not mapped\", \"Role in viral translation versus replication not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GSPT1 degradation mechanistically triggers the integrated stress response and selectively kills cancer cells, and whether its non-termination roles (apoptosis, proliferation signaling, mitophagy) depend on its termination activity, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Causal link from termination defect to ISR/eIF2alpha signaling not defined\", \"Structural model of the CRBN-GSPT1 ternary complex not in corpus\", \"Integration of GTPase, apoptotic, and signaling functions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"complexes\": [\n      \"eRF1-eRF3a translation termination complex\",\n      \"CRL4CRBN E3 ubiquitin ligase (neosubstrate)\"\n    ],\n    \"partners\": [\n      \"ETF1\",\n      \"PABPC1\",\n      \"CRBN\",\n      \"BIRC2\",\n      \"RAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}