{"gene":"G3BP2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2015,"finding":"G3BP2 sequesters TWIST1 in the cytoplasm under low matrix stiffness; increasing matrix stiffness releases TWIST1 from G3BP2, allowing its nuclear translocation to drive EMT. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization, promoting invasion and metastasis.","method":"Co-immunoprecipitation, loss-of-function (knockdown), live-cell imaging, in vivo tumor models","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KD with defined phenotypic readouts in vitro and in vivo, replicated across multiple experimental contexts in one rigorous study","pmids":["25893917"],"is_preprint":false},{"year":2012,"finding":"G3BP2 forms homo-multimers and hetero-multimers with G3BP1, and both proteins are required for stress granule (SG) formation; single knockdown of either partially reduces SGs, while double knockdown significantly reduces SG-positive cells. Overexpression of G3BP2 alone is sufficient to induce SG formation without stress stimuli.","method":"siRNA knockdown, co-immunoprecipitation, overexpression, immunofluorescence (SG counting)","journal":"Genes to Cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus gain- and loss-of-function with defined SG phenotype, independently consistent with G3BP1 literature","pmids":["23279204"],"is_preprint":false},{"year":2014,"finding":"G3BP2 (together with G3BP1 and CAPRIN1) is required for efficient translation of interferon-stimulated gene (ISG) mRNAs including PKR and IFITM2; dengue virus sfRNA acts as a molecular sponge that binds G3BP2 and inhibits this translational regulatory activity.","method":"siRNA knockdown, polysome/translation assays, RNA pulldown (sfRNA-protein interaction), ISG protein accumulation assays","journal":"PLoS Pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with defined translational phenotype plus RNA pulldown demonstrating direct sfRNA binding, multiple orthogonal methods in one study","pmids":["24992036"],"is_preprint":false},{"year":2015,"finding":"CHIKV nsP3 interacts with G3BP2 (and G3BP1) in cytoplasmic foci that differ from canonical SGs. Simultaneous depletion of G3BP1 and G3BP2 reduces viral RNA levels, CHIKV protein expression, and progeny titers, suggesting G3BPs facilitate the switch from viral genome translation to amplification early in infection.","method":"Co-immunoprecipitation (nsP3-G3BP2 interaction), siRNA double knockdown, viral RNA quantification, viral titer assays, immunofluorescence co-localization","journal":"Journal of Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus double-KD with multiple quantitative viral replication phenotypes, consistent with parallel finding from Sindbis virus paper","pmids":["25653451"],"is_preprint":false},{"year":2010,"finding":"G3BP2 (and G3BP1) physically associate with Sindbis virus nsP4 (RNA-dependent RNA polymerase) throughout infection and play an overlapping role in limiting SINV replication events.","method":"Affinity purification of FLAG-tagged nsP4 complexes followed by proteomic (MS) analysis, functional depletion assays","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome from tagged viral protein in infected cells, single lab with follow-up depletion phenotype","pmids":["20392851"],"is_preprint":false},{"year":2017,"finding":"Androgen receptor (AR) transcriptionally induces G3BP2 expression; elevated G3BP2 interacts with the SUMO-E3 ligase RanBP2 to promote SUMO-mediated cytoplasmic export of p53, thereby inhibiting p53 tumor suppressor activity and driving prostate cancer progression.","method":"ChIP, siRNA knockdown, subcellular fractionation/immunofluorescence for p53 localization, in vivo xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for AR-mediated induction, Co-IP for G3BP2-RanBP2 complex, KD with p53 nuclear/cytoplasmic phenotype in vitro and in vivo xenograft, multiple orthogonal methods","pmids":["28692047"],"is_preprint":false},{"year":2018,"finding":"TRIM25 interacts with G3BP2 protein complex and is important for G3BP2/RanBP2-mediated p53 nuclear export and sumoylation; TRIM25 knockdown restores nuclear p53 and activates downstream p53 signaling for cell cycle arrest and apoptosis.","method":"Co-immunoprecipitation, siRNA knockdown, cell cycle/apoptosis assays, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating TRIM25-G3BP2 interaction, KD phenotype in vitro and in vivo, single lab","pmids":["29379164"],"is_preprint":false},{"year":2018,"finding":"USP10 physically interacts with G3BP2 in stress granules and maintains G3BP2 protein stability by reducing its polyubiquitylation (deubiquitination). USP10 knockdown reduces G3BP2 levels, relieves G3BP2-dependent p53 nuclear export suppression, and decreases cell growth.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, protein stability assays","journal":"Molecular Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for USP10-G3BP2 interaction, ubiquitination assay demonstrating deubiquitination, KD phenotype; single lab, two orthogonal methods","pmids":["29378906"],"is_preprint":false},{"year":2017,"finding":"G3BP2 stabilizes SART3 mRNA, leading to increased expression of pluripotency transcription factors Oct-4 and Nanog, thereby regulating breast tumor-initiating cell (TIC) activity.","method":"Chemical screening identifying G3BP2 as a binding partner of compound C108, mRNA stability assays, knockdown/overexpression with TIC phenotypic readouts","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — small-molecule pulldown for target ID, mRNA stability assays, functional KD; single lab but multiple methods","pmids":["28096337"],"is_preprint":false},{"year":2012,"finding":"PKCα directly interacts with G3BP2 via its regulatory domain (binding to the C-terminal RNA-binding domain of G3BP2) in an RNA-independent manner; PKCα can phosphorylate G3BP2 in vitro. Both proteins co-localize in stress granules during cellular stress, and PKCα knockdown suppresses heat shock-induced SG assembly.","method":"Co-immunoprecipitation with/without RNase treatment, recombinant protein interaction assay, in vitro kinase assay, siRNA knockdown, immunofluorescence","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with recombinant proteins, domain-mapping by RNase-resistant Co-IP, KD with SG phenotype; multiple orthogonal methods in one study","pmids":["22536444"],"is_preprint":false},{"year":2012,"finding":"G3BP2 is methylated on arginine residues in response to Wnt3a signaling; this methylation acts as a switch regulating Wnt3a-stimulated LRP6 phosphorylation and canonical Wnt-β-catenin signaling. G3BP2 is a dishevelled-associated protein, and its knockdown or methylation-deficient mutants attenuate LRP6 phosphorylation.","method":"Co-immunoprecipitation (G3BP2-dishevelled), methyltransferase inhibitor treatment, methylation-deficient mutant expression, siRNA knockdown, LRP6 phosphorylation assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex membership, mutant rescue experiment for methylation function, pharmacological inhibition, single lab with multiple orthogonal methods","pmids":["22357953"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the G3BP2 NTF2-like domain in complex with an FGDF-motif peptide at 2.75 Å resolution; the domain forms a homodimer structurally similar to G3BP1 and Rasputin NTF2-like domains. The FGDF peptide binds via hydrophobic interactions to a symmetry-related molecule, revealing a binding mode distinct from that predicted by molecular modeling.","method":"X-ray crystallography","journal":"Biochemical and Biophysical Research Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at defined resolution with peptide-bound complex; single lab but Tier 1 method","pmids":["26410532"],"is_preprint":false},{"year":2017,"finding":"G3BP2 directly interacts with IκBα and promotes nuclear accumulation of NF-κB p65 subunit, increasing NF-κB transcriptional activity. G3BP2 overexpression induces cardiomyocyte hypertrophy that is suppressed by NF-κB inhibition or p65 knockdown, placing G3BP2 upstream of NF-κB in hypertrophic signaling.","method":"Co-immunoprecipitation (G3BP2-IκBα), overexpression/knockdown in neonatal rat cardiomyocytes, NF-κB luciferase reporter assay, immunofluorescence for p65 localization","journal":"Acta Pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct G3BP2-IκBα interaction, epistasis by NF-κB inhibition reversing G3BP2-induced hypertrophy, single lab","pmids":["28816235"],"is_preprint":false},{"year":2019,"finding":"Foot-and-mouth disease virus leader protease (Lpro) cleaves G3BP2 (and G3BP1) but not TIA-1, thereby suppressing stress granule formation. This cleavage activity is conserved in equine rhinitis A virus Lpro. Lpro does not affect PKR or eIF2α phosphorylation, indicating it acts on SG scaffolding proteins directly rather than upstream signaling.","method":"Recombinant chimeric virus system, immunoblot for G3BP2 cleavage, SG formation assay, PKR/eIF2α phosphorylation assay","journal":"Journal of Virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cleavage demonstrated biochemically, mechanistic dissection via negative result for upstream kinases, validated across two related viruses (replicated in orthologous system)","pmids":["30404792"],"is_preprint":false},{"year":2021,"finding":"MG53 (TRIM72) physically interacts with G3BP2 via its TRIM domain and induces nuclear translocation of G3BP2, blocking stress granule formation. Knockdown of MG53 enhances NSCLC cell proliferation/migration; the anti-proliferative effect of recombinant MG53 is abolished by G3BP2 knockout, placing G3BP2 as an essential downstream effector.","method":"Co-immunoprecipitation (MG53-G3BP2 via TRIM domain), shRNA knockdown, live cell imaging, in vivo allograft/xenograft mouse models","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain identification, KO epistasis showing G3BP2 requirement, in vivo models; single lab","pmids":["34521423"],"is_preprint":false},{"year":2022,"finding":"RIOK1 kinase directly interacts with G3BP2 and phosphorylates it at Thr226; this phosphorylation increases G3BP2 activity and facilitates MDM2-mediated ubiquitination and degradation of p53, thereby suppressing p53 signaling and promoting radioresistance in colorectal cancer.","method":"Co-immunoprecipitation, in vitro kinase assay with phospho-site identification, ubiquitination assay, siRNA/pharmacological inhibition, in vivo tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying specific phosphorylation site, Co-IP, ubiquitination assay demonstrating downstream consequence on p53; multiple orthogonal methods in single lab","pmids":["35589951"],"is_preprint":false},{"year":2021,"finding":"G3BP2 upregulates PD-L1 expression under stress conditions by stabilizing PD-L1 mRNA; genetic repression of G3BP2 or treatment with compound C108 (which binds G3BP2) leads to enhanced PD-L1 mRNA degradation, decreased PD-L1 protein, and increased CD8+ T cell infiltration in tumors.","method":"G3BP2 knockdown/C108 treatment, mRNA stability assays, in vivo tumor immunology (CD8+ T cell analysis, survival)","journal":"Molecular Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with mRNA stability readout mechanistically linking G3BP2 to PD-L1 mRNA stability, in vivo immunological phenotype; single lab","pmids":["33525064"],"is_preprint":false},{"year":2023,"finding":"G3BP2 directly interacts with Tau protein and masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. The G3BP2-Tau interaction is dramatically increased in multiple human tauopathies, and loss of G3BP2 in human neurons and brain organoids significantly elevates Tau pathology.","method":"Co-immunoprecipitation, in vitro aggregation assays, G3BP2 knockout in human neurons and brain organoids, post-mortem human brain tissue analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro aggregation inhibition assay, domain-level interaction (MTBR masking), KO in human neuron models with defined pathology readout, validated in human disease tissue","pmids":["37385246"],"is_preprint":false},{"year":2021,"finding":"G3BP2 regulates HDGF mRNA stability by directly binding to HDGF mRNA transcript; loss of G3BP2 reduces HDGF expression and suppresses ESCC cell migration, and HDGF re-expression rescues the G3BP2 depletion phenotype.","method":"RNA-seq, RNA immunoprecipitation (RIP), siRNA knockdown, rescue experiment with HDGF overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrating direct G3BP2-HDGF mRNA binding, epistasis rescue experiment, single lab","pmids":["34782720"],"is_preprint":false},{"year":2021,"finding":"G3BP2 inhibits BAALC-AS1-mediated stabilization of c-Myc mRNA: BAALC-AS1 directly interacts with G3BP2 and blocks G3BP2-mediated degradation of c-Myc mRNA 3'-UTR, leading to c-Myc accumulation and ESCC cell proliferation.","method":"RNA immunoprecipitation, RNA pulldown assay, luciferase reporter (c-Myc 3'-UTR), siRNA knockdown","journal":"Cancer Communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and RNA pulldown for interaction, luciferase for functional consequence, single lab with multiple methods","pmids":["33476486"],"is_preprint":false},{"year":2023,"finding":"PRMT5 methylates G3BP2 at Arg468 (R468me2), which enhances its binding to the deubiquitinase USP7; USP7 then deubiquitinates and stabilizes G3BP2. Stabilized G3BP2 activates ACLY to stimulate de novo lipogenesis and tumorigenesis in head and neck squamous carcinoma.","method":"Co-immunoprecipitation, methylation site identification (R468me2), deubiquitination assays, PRMT5 inhibitor/KD experiments, ACLY activity assays, in vivo tumor models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM site identified, Co-IP for USP7-G3BP2 interaction, deubiquitination assay, downstream ACLY pathway; single lab, multiple methods","pmids":["36878903"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2 nucleocapsid (N) protein promotes the interaction between G3BP2 and TRIM25, forming a TRIM25-G3BP2-N protein interactome. This enhanced G3BP2-TRIM25 binding interferes with RIG-I-like receptor signaling, suppressing type I interferon production.","method":"Co-immunoprecipitation in SARS-CoV-2-infected cells, proteomic interactome analysis, IFN production assay","journal":"Vaccines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating N protein-promoted G3BP2-TRIM25 complex, IFN assay showing functional consequence; single lab","pmids":["36560452"],"is_preprint":false},{"year":2025,"finding":"G3BP1 and G3BP2 redundantly suppress SARS-CoV-2 replication; ablation of both G3BP1 and G3BP2 enhances SARS-CoV-2 replication. The interaction between G3BP1/G3BP2 and the viral N protein disrupts stress granule formation, and specific residues required for this interaction were confirmed.","method":"CRISPR knockout of G3BP1 and G3BP2, viral replication assay, Co-IP/interaction mapping for N protein binding residues, SG formation assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO with viral replication phenotype, interaction residue mapping; single lab","pmids":["40733530"],"is_preprint":false},{"year":2024,"finding":"MAP4K4 phosphorylates G3BP2 at Thr227, triggered by cellular dipeptides imported via PEPT1; this phosphorylation enhances G3BP2 activity and promotes HCC cell metastasis.","method":"Co-immunoprecipitation (PEPT1-MAP4K4-G3BP2 axis), phosphorylation site identification (Thr227), siRNA/overexpression experiments, in vivo metastasis models","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific phosphorylation site identified, Co-IP for complex, in vivo metastasis validation; single lab","pmids":["38639383"],"is_preprint":false},{"year":2023,"finding":"G3BP2 binds PDIA3 mRNA and recruits it into stress granules, increasing PDIA3 mRNA stability but attenuating its translation, which promotes DKC1 expression. DKC1 in turn binds hENT mRNA and inhibits its expression, enhancing gemcitabine resistance in pancreatic ductal adenocarcinoma.","method":"RNA immunoprecipitation, stress granule isolation, gene expression analysis upon G3BP2 KD/OE, rescue experiments","journal":"Acta Pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP demonstrating G3BP2-PDIA3 mRNA binding, pathway epistasis; single lab with multiple methods","pmids":["39289547"],"is_preprint":false},{"year":2024,"finding":"PSF interacts with G3BP2 in the nucleus and in stress granules; their cooperative action stabilizes target pre-mRNA transcripts and sustains neuronal cell viability. Both PSF and G3BP2 levels are decreased in aged and Alzheimer's disease brains.","method":"Co-immunoprecipitation (PSF-G3BP2 nuclear interaction), RNA-seq, qRT-PCR for mRNA stability, aged mouse brain and human AD brain tissue analysis","journal":"Aging Cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for nuclear PSF-G3BP2 complex, mRNA stability correlation; single lab","pmids":["39155453"],"is_preprint":false},{"year":2019,"finding":"α-Parvin interacts with G3BP2; when α-parvin is present, it prevents G3BP2 interaction with TWIST1. Knockdown of α-parvin promotes G3BP2-TWIST1 interaction, increases ubiquitination and proteasome-dependent degradation of TWIST1, reducing TWIST1 levels and downstream signaling. G3BP2 depletion reverses the suppression of TWIST1 caused by α-parvin loss.","method":"Co-immunoprecipitation (α-parvin-G3BP2 and G3BP2-TWIST1), ubiquitination assay, domain mutant rescue, siRNA knockdown, in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for both complexes, ubiquitination assay, domain mutant rescue, epistasis; single lab","pmids":["30804457"],"is_preprint":false},{"year":2020,"finding":"G3BP2 regulates IκBα localization in endothelial cells; knockdown of G3BP2 reduces ox-LDL-induced inflammation via controlling IκBα localization, and G3bp2 knockout in ApoE-/- mice decreases atherosclerotic lesions with reduced pro-inflammatory cytokines.","method":"siRNA knockdown, Co-IP (G3BP2-IκBα), subcellular fractionation for IκBα localization, in vivo ApoE-/- mouse model","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for G3BP2-IκBα interaction, KD with IκBα localization readout, in vivo KD model; single lab","pmids":["32919187"],"is_preprint":false},{"year":2021,"finding":"Loss of G3BP2 in endothelial cells exposed to oscillatory shear stress increases YAP nucleocytoplasmic shuttling and phosphorylation, thereby diminishing OSS-induced inflammation. G3bp2 knockout in ApoE-/- mice decreases atherosclerotic lesions by protecting endothelial barrier function and reducing monocyte adhesion.","method":"siRNA/shRNA knockdown, partial ligation mouse model, RNA-seq, YAP localization/phosphorylation assays, in vivo G3bp2 Apoe double-knockout","journal":"Genes & Diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined phenotype, YAP pathway placement via phosphorylation/localization; single lab","pmids":["36157502"],"is_preprint":false},{"year":2023,"finding":"G3BP2 recruits lysosomal TSC2 to suppress mTORC1 under low-lactate stress; HDAC6 deacetylates TSC2 to sustain its stability and associates with G3BP2 to facilitate TSC2 recruitment, forming an HDAC6-G3BP2 complex that drives mTORC1 inhibition. HDAC6's microtubule retrograde transport activity promotes perinuclear mTOR distribution under stress.","method":"Co-immunoprecipitation (G3BP2-HDAC6-TSC2 complex), mTORC1 activity assays, HDAC6 deacetylation assay, live cell imaging of mTOR distribution","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for HDAC6-G3BP2-TSC2 complex, enzymatic deacetylation assay, pathway phenotype; single lab","pmids":["36823378"],"is_preprint":false},{"year":2026,"finding":"Cereblon (CRBN) can be directed by molecular glue degraders (MGDs) to ubiquitinate and degrade G3BP2 as a neosubstrate. The ternary complex structure reveals G3BP2 engages an unconventional binding site on the CRBN LON domain (not the canonical CULT domain G-loop), and CRBN mimics an endogenous binding partner of G3BP2 by exploiting a pre-existing PPI hotspot on G3BP2.","method":"Crystal/structural analysis of ternary complex, biochemical ubiquitination assay, proteomics","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination of ternary complex at defined resolution plus biochemical validation of degradation, novel binding mode established","pmids":["41559416"],"is_preprint":false},{"year":2025,"finding":"G3BPs (G3BP1 and G3BP2) and stress granules are necessary and sufficient to reinforce the integrated stress response translation program: they help prioritize translation of stress-resistant mRNAs enriched in SGs and suppress global cytosolic translation during stress, demonstrated using optogenetic tools and spike-normalized ribosome profiling.","method":"Optogenetic SG induction, spike-normalized ribosome profiling, G3BP1/2 double knockout, mRNA enrichment analysis in SGs","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ribosome profiling with optogenetic tools and KO in single lab; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"G3BP2 promotes ubiquitin-mediated degradation of STAT1; a lncRNA (LINC2781) directly binds G3BP2 and prevents this G3BP2-mediated STAT1 degradation through ubiquitination, thereby activating JAK-STAT signaling and antiviral ISG expression.","method":"Co-immunoprecipitation (G3BP2-STAT1 and LINC2781-G3BP2), ubiquitination assay, siRNA knockdown, ISG expression assay, in vivo mouse infection model","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating G3BP2-STAT1 interaction and lncRNA competition, ubiquitination assay; single lab","pmids":["40626722"],"is_preprint":false},{"year":2026,"finding":"G3BP2 acetylation at lysine 76 (K76), catalyzed by p300 and reversed by HDAC6, enhances G3BP2 binding to PABPC1 and PD-L1 mRNA, increasing PD-L1 mRNA stability and PD-L1 protein expression, thereby promoting immune evasion in colorectal cancer.","method":"Co-immunoprecipitation (G3BP2-PABPC1), RNA immunoprecipitation (G3BP2-PD-L1 mRNA), acetylation site mutagenesis, p300/HDAC6 writer-eraser identification, mRNA stability assay, in vivo immunocompetent mouse models","journal":"Cell Communication and Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM site identified with writer (p300) and eraser (HDAC6), Co-IP and RIP for effector complex, in vivo validation; single lab","pmids":["41906099"],"is_preprint":false},{"year":2025,"finding":"ROBO1 interacts with eIF3A and G3BP2 after irradiation, forming a hetero-complex that triggers lysosome-mediated eIF3A degradation; G3BP2 knockdown abrogates ROBO1's effect on eIF3A instability, placing G3BP2 as an essential component of this degradation complex.","method":"Co-immunoprecipitation, mass spectrometry (complex identification), siRNA knockdown epistasis, lysosomal inhibitor experiments","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified complex, KD epistasis demonstrating G3BP2 requirement; single lab","pmids":["40188129"],"is_preprint":false},{"year":2025,"finding":"EPS8L2 increases YBX1 phosphorylation by enhancing YBX1's interaction with S6K1; phosphorylated YBX1 translocates to the nucleus and initiates G3BP2 transcription, activating the MAPK signaling pathway to drive colorectal cancer proliferation and metastasis.","method":"Co-immunoprecipitation (EPS8L2-YBX1-S6K1), YBX1 phosphorylation assay, nuclear translocation assay, G3BP2 promoter-reporter, MAPK pathway activation assay, in vivo AOM/DSS mouse model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, promoter reporter, in vivo model; single lab with multiple methods placing G3BP2 downstream of the EPS8L2-YBX1 axis","pmids":["40783393"],"is_preprint":false},{"year":2025,"finding":"G3BP2 suppresses p53 signaling in rheumatoid arthritis fibroblast-like synoviocytes (FLSs) by promoting p53 ubiquitination; G3BP2 silencing or compound C108 treatment reduces p53 ubiquitination, increases nuclear p53 levels, and suppresses RA-FLS migration and invasion. The p53 inhibitor PFT-α reverses the C108 inhibitory effect, confirming epistatic placement.","method":"siRNA knockdown, compound C108 treatment, ubiquitination assay for p53, RNA sequencing, p53 inhibitor epistasis, in vivo adjuvant-induced arthritis rat model","journal":"International Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay, epistasis via p53 inhibitor rescue, in vivo model; single lab","pmids":["41338150"],"is_preprint":false}],"current_model":"G3BP2 is a multifunctional RNA-binding protein and core stress granule scaffold that: (1) sequesters cytoplasmic binding partners (TWIST1, p53) to control their nuclear translocation in response to mechanical or hormonal signals; (2) stabilizes or destabilizes specific mRNA targets (SART3, HDGF, PD-L1, c-Myc) via direct mRNA binding, with post-translational modifications (arginine methylation by PRMT5, phosphorylation at Thr226/Thr227 by RIOK1/MAP4K4, acetylation at K76 by p300/HDAC6, deubiquitination by USP7) fine-tuning its activity; (3) facilitates stress granule assembly through NTF2-like domain-mediated homo- and heterodimerization and FGDF-motif interactions with partner proteins; (4) supports replication of multiple RNA viruses (alphaviruses, SARS-CoV-2) while being proteolytically targeted by viral proteases (FMDV Lpro) to disrupt SG-mediated antiviral defenses; and (5) inhibits Tau aggregation by masking the microtubule-binding region of Tau, serving as a natural defense in tauopathies."},"narrative":{"mechanistic_narrative":"G3BP2 is a multifunctional RNA-binding scaffold protein that nucleates stress granule (SG) assembly and couples cytoplasmic mRNA fate and protein sequestration to mechanical, hormonal, and stress signals [PMID:23279204, PMID:25893917]. Through its NTF2-like domain it forms homo- and hetero-multimers with G3BP1 and engages FGDF-motif partners, with the domain crystallizing as a homodimer that binds FGDF peptides via a hydrophobic surface [PMID:26410532]; both G3BPs are required for efficient SG formation, and G3BP2 overexpression alone induces SGs without stress [PMID:23279204]. As a cytoplasmic sequestering platform, G3BP2 retains TWIST1 under low matrix stiffness to restrain EMT and metastasis [PMID:25893917], and drives RanBP2/TRIM25-dependent SUMOylation and nuclear export of p53 to suppress its tumor-suppressor activity downstream of androgen receptor induction [PMID:28692047, PMID:29379164]. G3BP2 additionally controls the stability and translation of specific transcripts—stabilizing SART3, HDGF, and PD-L1 mRNAs while degrading c-Myc mRNA—to influence stemness, migration, and immune evasion [PMID:28096337, PMID:34782720, PMID:33525064, PMID:33476486]. Its activity is tuned by a layered code of post-translational modifications: phosphorylation at Thr226/Thr227 by RIOK1 and MAP4K4, arginine methylation at R468 by PRMT5 (promoting USP7-mediated deubiquitination and stabilization), and K76 acetylation by p300 reversed by HDAC6 (enhancing PABPC1 and PD-L1 mRNA binding) [PMID:35589951, PMID:38639383, PMID:36878903, PMID:41906099]. In antiviral immunity G3BP2 supports SG-based defenses and is a target for viral antagonism: it associates with alphavirus replication proteins, is proteolytically cleaved by foot-and-mouth disease virus Lpro to disable SGs, and redundantly with G3BP1 restricts SARS-CoV-2 whose N protein disrupts the G3BP–SG axis [PMID:20392851, PMID:25653451, PMID:30404792, PMID:40733530]. G3BP2 also directly binds Tau, masking its microtubule-binding region to inhibit aggregation, and its loss elevates Tau pathology in human neurons [PMID:37385246].","teleology":[{"year":2010,"claim":"Established the first physical link between G3BP2 and viral RNA replication machinery, raising the question of whether host SG proteins are co-opted or antiviral during alphavirus infection.","evidence":"Affinity purification/MS of FLAG-tagged Sindbis virus nsP4 with functional depletion in infected cells","pmids":["20392851"],"confidence":"Medium","gaps":["Interaction identified by MS without direct binary binding validation","Whether G3BP2 promotes or limits replication not cleanly resolved here"]},{"year":2012,"claim":"Defined G3BP2 as a core SG scaffold by showing it multimerizes with G3BP1 and is itself sufficient to induce SGs, identifying the molecular building block of granule assembly.","evidence":"Reciprocal Co-IP, single/double siRNA knockdown, overexpression, and SG immunofluorescence counting","pmids":["23279204"],"confidence":"High","gaps":["Did not resolve the structural basis of multimerization","RNA targets within SGs not defined"]},{"year":2012,"claim":"Connected G3BP2 to signal-dependent regulation, identifying PKCα as a direct binding kinase and arginine methylation as a Wnt-responsive switch, indicating its activity is post-translationally controlled.","evidence":"RNase-resistant Co-IP, recombinant in vitro kinase assay, methyltransferase inhibition and methylation-deficient mutants with LRP6 phosphorylation readout","pmids":["22536444","22357953"],"confidence":"High","gaps":["PKCα phosphorylation sites on G3BP2 not mapped","Functional consequence of PKCα phosphorylation on SG dynamics unresolved"]},{"year":2014,"claim":"Showed G3BP2 acts in translational control of antiviral ISG mRNAs and is a target of flaviviral subversion, framing it as both a host defense factor and a viral target.","evidence":"siRNA knockdown with polysome/translation assays and sfRNA RNA pulldown demonstrating direct binding","pmids":["24992036"],"confidence":"High","gaps":["mRNA-binding determinants on G3BP2 not mapped","Mechanism by which sfRNA sponging blocks translation not detailed"]},{"year":2015,"claim":"Defined G3BP2 as a mechanotransducer that sequesters TWIST1 in the cytoplasm, answering how matrix stiffness gates EMT and metastasis.","evidence":"Co-IP, knockdown, live-cell imaging, and in vivo tumor models","pmids":["25893917"],"confidence":"High","gaps":["Molecular sensor of stiffness that releases TWIST1 not identified","Binding interface on G3BP2 for TWIST1 not mapped"]},{"year":2015,"claim":"Resolved the structural basis of partner engagement by crystallizing the G3BP2 NTF2-like domain bound to an FGDF peptide, establishing the homodimeric module that underlies SG and viral protein interactions.","evidence":"X-ray crystallography of NTF2-like/FGDF complex at 2.75 Å","pmids":["26410532"],"confidence":"High","gaps":["Full-length protein architecture and RNA-binding domain not structurally defined","How dimerization translates to granule condensation not addressed"]},{"year":2017,"claim":"Placed G3BP2 in an androgen-receptor-driven oncogenic axis that exports p53, explaining how its overexpression inactivates a tumor suppressor in prostate cancer.","evidence":"ChIP for AR induction, Co-IP for G3BP2-RanBP2, fractionation/IF for p53 localization, xenografts","pmids":["28692047"],"confidence":"High","gaps":["Direct G3BP2 contribution to SUMO-ligase activity not biochemically defined","Generality beyond prostate cancer untested at this stage"]},{"year":2017,"claim":"Extended the mRNA-stabilizing role of G3BP2 to cancer stemness by linking it to SART3 mRNA and pluripotency factors.","evidence":"Chemical-probe (C108) target ID, mRNA stability assays, knockdown/overexpression with TIC readouts","pmids":["28096337"],"confidence":"Medium","gaps":["Direct G3BP2-SART3 mRNA binding sites not mapped","Single lab"]},{"year":2018,"claim":"Identified TRIM25 and USP10 as regulators of the G3BP2-p53 export axis and of G3BP2 stability, revealing how complex membership and deubiquitination sustain its oncogenic function.","evidence":"Co-IP, ubiquitination assays, knockdown with p53 localization and growth phenotypes, xenografts","pmids":["29379164","29378906"],"confidence":"Medium","gaps":["E3 ligase opposing USP10 not identified","Reciprocal validation of complexes limited to single labs"]},{"year":2019,"claim":"Demonstrated that viral proteases directly disable G3BP2 to dismantle SG defenses, distinguishing scaffold cleavage from upstream stress kinase signaling.","evidence":"Recombinant chimeric virus, immunoblot for cleavage, SG assays, PKR/eIF2α phosphorylation controls, replicated in a second virus","pmids":["30404792"],"confidence":"High","gaps":["Precise cleavage site within G3BP2 not specified here","Consequences for non-SG functions of G3BP2 untested"]},{"year":2019,"claim":"Showed α-parvin gates the G3BP2-TWIST1 interaction and TWIST1 degradation, refining how upstream adhesion-linked factors control the mechanosensitive sequestration circuit.","evidence":"Co-IP of both complexes, ubiquitination assay, domain-mutant rescue, knockdown, in vivo tumor models","pmids":["30804457"],"confidence":"Medium","gaps":["Mechanism by which α-parvin displaces TWIST1 not structurally defined","Single lab"]},{"year":2020,"claim":"Linked G3BP2 to inflammatory signaling by controlling IκBα localization and NF-κB activity in vascular and cardiac contexts, broadening its role beyond cancer and stress granules.","evidence":"Co-IP (G3BP2-IκBα), knockdown/overexpression, NF-κB reporters, fractionation, and ApoE-/- mouse models","pmids":["28816235","32919187"],"confidence":"Medium","gaps":["Whether G3BP2-IκBα binding directly alters IκBα degradation unresolved","Tissue specificity of the effect not delineated"]},{"year":2021,"claim":"Expanded the G3BP2 mRNA regulon to HDGF, PD-L1, and c-Myc, establishing it as a sequence-selective controller of transcript stability driving migration, immune evasion, and proliferation.","evidence":"RIP/RNA pulldown, mRNA stability and luciferase reporter assays, knockdown with rescue, in vivo tumor immunology","pmids":["34782720","33525064","33476486"],"confidence":"Medium","gaps":["Binding motif distinguishing stabilized vs degraded targets unknown","Each target characterized in a single tumor context"]},{"year":2021,"claim":"Identified MG53/TRIM72 as a factor that drives nuclear translocation of G3BP2 to block SG formation, positioning G3BP2 as an essential downstream effector of an anti-proliferative pathway.","evidence":"Co-IP with TRIM domain mapping, shRNA knockdown, live imaging, allograft/xenograft models","pmids":["34521423"],"confidence":"Medium","gaps":["Mechanism of forced nuclear import not defined","Single lab"]},{"year":2022,"claim":"Established phosphorylation by RIOK1 at Thr226 as an activating modification that amplifies G3BP2-driven p53 degradation and radioresistance, opening the post-translational regulatory layer.","evidence":"Co-IP, in vitro kinase assay with site ID, ubiquitination assay, inhibition, in vivo tumor models","pmids":["35589951"],"confidence":"High","gaps":["How phosphorylation mechanistically enhances p53 degradation not structurally resolved","Single tumor model"]},{"year":2023,"claim":"Revealed a PRMT5/USP7 arginine-methylation/deubiquitination axis stabilizing G3BP2 and a metabolic output via ACLY, integrating PTM control with lipogenesis and tumorigenesis.","evidence":"Co-IP, methylation site ID (R468me2), deubiquitination assays, PRMT5 inhibition, ACLY activity, in vivo models","pmids":["36878903"],"confidence":"Medium","gaps":["How stabilized G3BP2 activates ACLY mechanistically unclear","Single lab"]},{"year":2023,"claim":"Showed G3BP2 directly binds Tau and masks its microtubule-binding region to inhibit aggregation, defining a protective function in tauopathy.","evidence":"Co-IP, in vitro aggregation assays, KO in human neurons and brain organoids, post-mortem tissue analysis","pmids":["37385246"],"confidence":"High","gaps":["Structural basis of MTBR masking not resolved","Whether SG assembly is required for the protective effect unclear"]},{"year":2023,"claim":"Connected G3BP2 to mTORC1 regulation and stress-dependent mRNA-translation reprogramming, showing it recruits TSC2 via an HDAC6 complex and partitions transcripts in SGs.","evidence":"Co-IP of HDAC6-G3BP2-TSC2 complex, mTORC1 activity and deacetylation assays, RIP, SG isolation","pmids":["36823378","39289547"],"confidence":"Medium","gaps":["Direct vs scaffolding role in TSC2 recruitment not separated","Selectivity of mRNA partitioning into SGs not generalized"]},{"year":2024,"claim":"Identified MAP4K4 phosphorylation at Thr227 downstream of dipeptide import as a metabolic-stimulus-driven activating modification promoting metastasis.","evidence":"Co-IP of PEPT1-MAP4K4-G3BP2 axis, phospho-site ID, knockdown/overexpression, in vivo metastasis models","pmids":["38639383"],"confidence":"Medium","gaps":["Relationship between Thr226 and Thr227 phosphorylation events not reconciled","Single lab"]},{"year":2024,"claim":"Documented a nuclear PSF-G3BP2 complex stabilizing pre-mRNAs to support neuronal viability, extending G3BP2 function into the nucleus and neurodegeneration.","evidence":"Co-IP of nuclear complex, RNA-seq, qRT-PCR stability, aged mouse and human AD brain tissue","pmids":["39155453"],"confidence":"Medium","gaps":["Direct vs indirect nuclear RNA targets not defined","Causal link between reduced G3BP2 and AD pathology not established"]},{"year":2025,"claim":"Resolved the redundancy and antiviral logic of G3BPs against SARS-CoV-2 and showed the N protein hijacks the G3BP2-TRIM25 interface to suppress interferon, clarifying virus-host competition at the SG scaffold.","evidence":"CRISPR double KO with viral replication assays, interaction-residue mapping, IFN production assays in infected cells","pmids":["40733530","36560452"],"confidence":"Medium","gaps":["Quantitative split of G3BP1 vs G3BP2 contributions not resolved","Whether SG disruption alone explains the IFN phenotype unclear"]},{"year":2025,"claim":"Implicated G3BP2 in ubiquitin/lysosome-mediated turnover of signaling proteins (STAT1, eIF3A), with lncRNAs competing for G3BP2 to tune antiviral and stress responses.","evidence":"Co-IP, ubiquitination assays, MS complex ID, knockdown epistasis, ISG/lysosomal inhibitor experiments, in vivo infection","pmids":["40626722","40188129"],"confidence":"Medium","gaps":["Whether G3BP2 acts as adaptor or directly recruits ligases unresolved","These degradation roles each rest on single studies"]},{"year":2026,"claim":"Defined acetylation at K76 (p300 writer, HDAC6 eraser) as a modification that boosts PABPC1 and PD-L1 mRNA binding, completing a multi-PTM control map governing G3BP2 mRNA targeting and immune evasion.","evidence":"Co-IP, RIP, acetylation site mutagenesis, writer/eraser identification, mRNA stability, immunocompetent mouse models","pmids":["41906099"],"confidence":"Medium","gaps":["Interplay between K76 acetylation and other PTMs not mapped","Single tumor type"]},{"year":2026,"claim":"Provided structural insight into G3BP2 degradability by showing cereblon molecular glues engage an unconventional LON-domain site exploiting a native PPI hotspot, establishing G3BP2 as a tractable degrader neosubstrate.","evidence":"Ternary complex structural analysis, biochemical ubiquitination assays, proteomics","pmids":["41559416"],"confidence":"High","gaps":["Identity of the endogenous partner mimicked by CRBN not confirmed","Functional consequence of induced G3BP2 degradation in cells not characterized here"]},{"year":null,"claim":"How the layered PTM code, partner sequestration, and selective mRNA stabilization/degradation are integrated to determine when G3BP2 protects (Tau, antiviral) versus promotes disease (oncogenic p53 export, immune evasion) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to specific mRNA target choice","Structural basis for full-length G3BP2 RNA recognition undefined","Determinants of nuclear vs cytoplasmic vs SG localization not mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,8,16,18,19,24,33]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,26,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,5,17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,31]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,25]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,18,19,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,16,22,32,33]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,9,29,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10,12,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,15,20,32,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,17,27]}],"complexes":["stress granule","G3BP1-G3BP2 multimer"],"partners":["G3BP1","TWIST1","RANBP2","TRIM25","USP10","HDAC6","PABPC1","TSC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UN86","full_name":"Ras GTPase-activating protein-binding protein 2","aliases":["GAP SH3 domain-binding protein 2"],"length_aa":482,"mass_kda":54.1,"function":"Scaffold protein that plays an essential role in cytoplasmic stress granule formation which acts as a platform for antiviral signaling (PubMed:23279204, PubMed:32302570, PubMed:32302571, PubMed:32302572). Plays an essential role in stress granule formation (PubMed:27022092, PubMed:32302570, PubMed:32302571, PubMed:32302572, PubMed:35977029). Stress granules are membraneless compartments that store mRNAs and proteins, such as stalled translation pre-initiation complexes, in response to stress (PubMed:32302570, PubMed:32302571, PubMed:32302572). Promotes formation of stress granules phase-separated membraneless compartment by undergoing liquid-liquid phase separation (LLPS) upon unfolded RNA-binding: functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9UN86/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/G3BP2","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138757","cell_line_id":"CID000066","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"G3BP1","stoichiometry":10.0},{"gene":"RPLP1","stoichiometry":10.0},{"gene":"CAPRIN1","stoichiometry":4.0},{"gene":"RPS28","stoichiometry":4.0},{"gene":"RPL30","stoichiometry":4.0},{"gene":"RPL8","stoichiometry":4.0},{"gene":"GNB2L1","stoichiometry":4.0},{"gene":"RPS26","stoichiometry":4.0},{"gene":"RPS25","stoichiometry":4.0},{"gene":"RPL23","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000066","total_profiled":1310},"omim":[{"mim_id":"620020","title":"G3BP STRESS GRANULE ASSEMBLY FACTOR 2; G3BP2","url":"https://www.omim.org/entry/620020"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/G3BP2"},"hgnc":{"alias_symbol":["KIAA0660"],"prev_symbol":[]},"alphafold":{"accession":"Q9UN86","domains":[{"cath_id":"3.10.450.50","chopping":"7-138","consensus_level":"high","plddt":95.058,"start":7,"end":138},{"cath_id":"3.30.70.330","chopping":"328-413","consensus_level":"high","plddt":80.0853,"start":328,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UN86","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UN86-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UN86-F1-predicted_aligned_error_v6.png","plddt_mean":65.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=G3BP2","jax_strain_url":"https://www.jax.org/strain/search?query=G3BP2"},"sequence":{"accession":"Q9UN86","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UN86.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UN86/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UN86"}},"corpus_meta":[{"pmid":"25893917","id":"PMC_25893917","title":"Matrix 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lncRNA LINC01554 facilitates esophageal squamous cell carcinoma metastasis through stabilizing HDGF transcript.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34782720","citation_count":25,"is_preprint":false},{"pmid":"32967107","id":"PMC_32967107","title":"FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32967107","citation_count":23,"is_preprint":false},{"pmid":"37385246","id":"PMC_37385246","title":"Increased G3BP2-Tau interaction in tauopathies is a natural defense against Tau aggregation.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/37385246","citation_count":22,"is_preprint":false},{"pmid":"33476486","id":"PMC_33476486","title":"BAALC-AS1/G3BP2/c-Myc feedback loop promotes cell proliferation in esophageal squamous cell 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Loss of G3BP2 leads to constitutive TWIST1 nuclear localization, promoting invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function (knockdown), live-cell imaging, in vivo tumor models\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KD with defined phenotypic readouts in vitro and in vivo, replicated across multiple experimental contexts in one rigorous study\",\n      \"pmids\": [\"25893917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"G3BP2 forms homo-multimers and hetero-multimers with G3BP1, and both proteins are required for stress granule (SG) formation; single knockdown of either partially reduces SGs, while double knockdown significantly reduces SG-positive cells. Overexpression of G3BP2 alone is sufficient to induce SG formation without stress stimuli.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, overexpression, immunofluorescence (SG counting)\",\n      \"journal\": \"Genes to Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus gain- and loss-of-function with defined SG phenotype, independently consistent with G3BP1 literature\",\n      \"pmids\": [\"23279204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"G3BP2 (together with G3BP1 and CAPRIN1) is required for efficient translation of interferon-stimulated gene (ISG) mRNAs including PKR and IFITM2; dengue virus sfRNA acts as a molecular sponge that binds G3BP2 and inhibits this translational regulatory activity.\",\n      \"method\": \"siRNA knockdown, polysome/translation assays, RNA pulldown (sfRNA-protein interaction), ISG protein accumulation assays\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with defined translational phenotype plus RNA pulldown demonstrating direct sfRNA binding, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24992036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CHIKV nsP3 interacts with G3BP2 (and G3BP1) in cytoplasmic foci that differ from canonical SGs. Simultaneous depletion of G3BP1 and G3BP2 reduces viral RNA levels, CHIKV protein expression, and progeny titers, suggesting G3BPs facilitate the switch from viral genome translation to amplification early in infection.\",\n      \"method\": \"Co-immunoprecipitation (nsP3-G3BP2 interaction), siRNA double knockdown, viral RNA quantification, viral titer assays, immunofluorescence co-localization\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus double-KD with multiple quantitative viral replication phenotypes, consistent with parallel finding from Sindbis virus paper\",\n      \"pmids\": [\"25653451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"G3BP2 (and G3BP1) physically associate with Sindbis virus nsP4 (RNA-dependent RNA polymerase) throughout infection and play an overlapping role in limiting SINV replication events.\",\n      \"method\": \"Affinity purification of FLAG-tagged nsP4 complexes followed by proteomic (MS) analysis, functional depletion assays\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome from tagged viral protein in infected cells, single lab with follow-up depletion phenotype\",\n      \"pmids\": [\"20392851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Androgen receptor (AR) transcriptionally induces G3BP2 expression; elevated G3BP2 interacts with the SUMO-E3 ligase RanBP2 to promote SUMO-mediated cytoplasmic export of p53, thereby inhibiting p53 tumor suppressor activity and driving prostate cancer progression.\",\n      \"method\": \"ChIP, siRNA knockdown, subcellular fractionation/immunofluorescence for p53 localization, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for AR-mediated induction, Co-IP for G3BP2-RanBP2 complex, KD with p53 nuclear/cytoplasmic phenotype in vitro and in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"28692047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM25 interacts with G3BP2 protein complex and is important for G3BP2/RanBP2-mediated p53 nuclear export and sumoylation; TRIM25 knockdown restores nuclear p53 and activates downstream p53 signaling for cell cycle arrest and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell cycle/apoptosis assays, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating TRIM25-G3BP2 interaction, KD phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"29379164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 physically interacts with G3BP2 in stress granules and maintains G3BP2 protein stability by reducing its polyubiquitylation (deubiquitination). USP10 knockdown reduces G3BP2 levels, relieves G3BP2-dependent p53 nuclear export suppression, and decreases cell growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, protein stability assays\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for USP10-G3BP2 interaction, ubiquitination assay demonstrating deubiquitination, KD phenotype; single lab, two orthogonal methods\",\n      \"pmids\": [\"29378906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"G3BP2 stabilizes SART3 mRNA, leading to increased expression of pluripotency transcription factors Oct-4 and Nanog, thereby regulating breast tumor-initiating cell (TIC) activity.\",\n      \"method\": \"Chemical screening identifying G3BP2 as a binding partner of compound C108, mRNA stability assays, knockdown/overexpression with TIC phenotypic readouts\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — small-molecule pulldown for target ID, mRNA stability assays, functional KD; single lab but multiple methods\",\n      \"pmids\": [\"28096337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PKCα directly interacts with G3BP2 via its regulatory domain (binding to the C-terminal RNA-binding domain of G3BP2) in an RNA-independent manner; PKCα can phosphorylate G3BP2 in vitro. Both proteins co-localize in stress granules during cellular stress, and PKCα knockdown suppresses heat shock-induced SG assembly.\",\n      \"method\": \"Co-immunoprecipitation with/without RNase treatment, recombinant protein interaction assay, in vitro kinase assay, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with recombinant proteins, domain-mapping by RNase-resistant Co-IP, KD with SG phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22536444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"G3BP2 is methylated on arginine residues in response to Wnt3a signaling; this methylation acts as a switch regulating Wnt3a-stimulated LRP6 phosphorylation and canonical Wnt-β-catenin signaling. G3BP2 is a dishevelled-associated protein, and its knockdown or methylation-deficient mutants attenuate LRP6 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (G3BP2-dishevelled), methyltransferase inhibitor treatment, methylation-deficient mutant expression, siRNA knockdown, LRP6 phosphorylation assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex membership, mutant rescue experiment for methylation function, pharmacological inhibition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22357953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the G3BP2 NTF2-like domain in complex with an FGDF-motif peptide at 2.75 Å resolution; the domain forms a homodimer structurally similar to G3BP1 and Rasputin NTF2-like domains. The FGDF peptide binds via hydrophobic interactions to a symmetry-related molecule, revealing a binding mode distinct from that predicted by molecular modeling.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at defined resolution with peptide-bound complex; single lab but Tier 1 method\",\n      \"pmids\": [\"26410532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"G3BP2 directly interacts with IκBα and promotes nuclear accumulation of NF-κB p65 subunit, increasing NF-κB transcriptional activity. G3BP2 overexpression induces cardiomyocyte hypertrophy that is suppressed by NF-κB inhibition or p65 knockdown, placing G3BP2 upstream of NF-κB in hypertrophic signaling.\",\n      \"method\": \"Co-immunoprecipitation (G3BP2-IκBα), overexpression/knockdown in neonatal rat cardiomyocytes, NF-κB luciferase reporter assay, immunofluorescence for p65 localization\",\n      \"journal\": \"Acta Pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct G3BP2-IκBα interaction, epistasis by NF-κB inhibition reversing G3BP2-induced hypertrophy, single lab\",\n      \"pmids\": [\"28816235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Foot-and-mouth disease virus leader protease (Lpro) cleaves G3BP2 (and G3BP1) but not TIA-1, thereby suppressing stress granule formation. This cleavage activity is conserved in equine rhinitis A virus Lpro. Lpro does not affect PKR or eIF2α phosphorylation, indicating it acts on SG scaffolding proteins directly rather than upstream signaling.\",\n      \"method\": \"Recombinant chimeric virus system, immunoblot for G3BP2 cleavage, SG formation assay, PKR/eIF2α phosphorylation assay\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cleavage demonstrated biochemically, mechanistic dissection via negative result for upstream kinases, validated across two related viruses (replicated in orthologous system)\",\n      \"pmids\": [\"30404792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MG53 (TRIM72) physically interacts with G3BP2 via its TRIM domain and induces nuclear translocation of G3BP2, blocking stress granule formation. Knockdown of MG53 enhances NSCLC cell proliferation/migration; the anti-proliferative effect of recombinant MG53 is abolished by G3BP2 knockout, placing G3BP2 as an essential downstream effector.\",\n      \"method\": \"Co-immunoprecipitation (MG53-G3BP2 via TRIM domain), shRNA knockdown, live cell imaging, in vivo allograft/xenograft mouse models\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain identification, KO epistasis showing G3BP2 requirement, in vivo models; single lab\",\n      \"pmids\": [\"34521423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RIOK1 kinase directly interacts with G3BP2 and phosphorylates it at Thr226; this phosphorylation increases G3BP2 activity and facilitates MDM2-mediated ubiquitination and degradation of p53, thereby suppressing p53 signaling and promoting radioresistance in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with phospho-site identification, ubiquitination assay, siRNA/pharmacological inhibition, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying specific phosphorylation site, Co-IP, ubiquitination assay demonstrating downstream consequence on p53; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"35589951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"G3BP2 upregulates PD-L1 expression under stress conditions by stabilizing PD-L1 mRNA; genetic repression of G3BP2 or treatment with compound C108 (which binds G3BP2) leads to enhanced PD-L1 mRNA degradation, decreased PD-L1 protein, and increased CD8+ T cell infiltration in tumors.\",\n      \"method\": \"G3BP2 knockdown/C108 treatment, mRNA stability assays, in vivo tumor immunology (CD8+ T cell analysis, survival)\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with mRNA stability readout mechanistically linking G3BP2 to PD-L1 mRNA stability, in vivo immunological phenotype; single lab\",\n      \"pmids\": [\"33525064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G3BP2 directly interacts with Tau protein and masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. The G3BP2-Tau interaction is dramatically increased in multiple human tauopathies, and loss of G3BP2 in human neurons and brain organoids significantly elevates Tau pathology.\",\n      \"method\": \"Co-immunoprecipitation, in vitro aggregation assays, G3BP2 knockout in human neurons and brain organoids, post-mortem human brain tissue analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro aggregation inhibition assay, domain-level interaction (MTBR masking), KO in human neuron models with defined pathology readout, validated in human disease tissue\",\n      \"pmids\": [\"37385246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"G3BP2 regulates HDGF mRNA stability by directly binding to HDGF mRNA transcript; loss of G3BP2 reduces HDGF expression and suppresses ESCC cell migration, and HDGF re-expression rescues the G3BP2 depletion phenotype.\",\n      \"method\": \"RNA-seq, RNA immunoprecipitation (RIP), siRNA knockdown, rescue experiment with HDGF overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrating direct G3BP2-HDGF mRNA binding, epistasis rescue experiment, single lab\",\n      \"pmids\": [\"34782720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"G3BP2 inhibits BAALC-AS1-mediated stabilization of c-Myc mRNA: BAALC-AS1 directly interacts with G3BP2 and blocks G3BP2-mediated degradation of c-Myc mRNA 3'-UTR, leading to c-Myc accumulation and ESCC cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation, RNA pulldown assay, luciferase reporter (c-Myc 3'-UTR), siRNA knockdown\",\n      \"journal\": \"Cancer Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and RNA pulldown for interaction, luciferase for functional consequence, single lab with multiple methods\",\n      \"pmids\": [\"33476486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT5 methylates G3BP2 at Arg468 (R468me2), which enhances its binding to the deubiquitinase USP7; USP7 then deubiquitinates and stabilizes G3BP2. Stabilized G3BP2 activates ACLY to stimulate de novo lipogenesis and tumorigenesis in head and neck squamous carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, methylation site identification (R468me2), deubiquitination assays, PRMT5 inhibitor/KD experiments, ACLY activity assays, in vivo tumor models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM site identified, Co-IP for USP7-G3BP2 interaction, deubiquitination assay, downstream ACLY pathway; single lab, multiple methods\",\n      \"pmids\": [\"36878903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2 nucleocapsid (N) protein promotes the interaction between G3BP2 and TRIM25, forming a TRIM25-G3BP2-N protein interactome. This enhanced G3BP2-TRIM25 binding interferes with RIG-I-like receptor signaling, suppressing type I interferon production.\",\n      \"method\": \"Co-immunoprecipitation in SARS-CoV-2-infected cells, proteomic interactome analysis, IFN production assay\",\n      \"journal\": \"Vaccines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating N protein-promoted G3BP2-TRIM25 complex, IFN assay showing functional consequence; single lab\",\n      \"pmids\": [\"36560452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"G3BP1 and G3BP2 redundantly suppress SARS-CoV-2 replication; ablation of both G3BP1 and G3BP2 enhances SARS-CoV-2 replication. The interaction between G3BP1/G3BP2 and the viral N protein disrupts stress granule formation, and specific residues required for this interaction were confirmed.\",\n      \"method\": \"CRISPR knockout of G3BP1 and G3BP2, viral replication assay, Co-IP/interaction mapping for N protein binding residues, SG formation assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO with viral replication phenotype, interaction residue mapping; single lab\",\n      \"pmids\": [\"40733530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAP4K4 phosphorylates G3BP2 at Thr227, triggered by cellular dipeptides imported via PEPT1; this phosphorylation enhances G3BP2 activity and promotes HCC cell metastasis.\",\n      \"method\": \"Co-immunoprecipitation (PEPT1-MAP4K4-G3BP2 axis), phosphorylation site identification (Thr227), siRNA/overexpression experiments, in vivo metastasis models\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific phosphorylation site identified, Co-IP for complex, in vivo metastasis validation; single lab\",\n      \"pmids\": [\"38639383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G3BP2 binds PDIA3 mRNA and recruits it into stress granules, increasing PDIA3 mRNA stability but attenuating its translation, which promotes DKC1 expression. DKC1 in turn binds hENT mRNA and inhibits its expression, enhancing gemcitabine resistance in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"RNA immunoprecipitation, stress granule isolation, gene expression analysis upon G3BP2 KD/OE, rescue experiments\",\n      \"journal\": \"Acta Pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP demonstrating G3BP2-PDIA3 mRNA binding, pathway epistasis; single lab with multiple methods\",\n      \"pmids\": [\"39289547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSF interacts with G3BP2 in the nucleus and in stress granules; their cooperative action stabilizes target pre-mRNA transcripts and sustains neuronal cell viability. Both PSF and G3BP2 levels are decreased in aged and Alzheimer's disease brains.\",\n      \"method\": \"Co-immunoprecipitation (PSF-G3BP2 nuclear interaction), RNA-seq, qRT-PCR for mRNA stability, aged mouse brain and human AD brain tissue analysis\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for nuclear PSF-G3BP2 complex, mRNA stability correlation; single lab\",\n      \"pmids\": [\"39155453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"α-Parvin interacts with G3BP2; when α-parvin is present, it prevents G3BP2 interaction with TWIST1. Knockdown of α-parvin promotes G3BP2-TWIST1 interaction, increases ubiquitination and proteasome-dependent degradation of TWIST1, reducing TWIST1 levels and downstream signaling. G3BP2 depletion reverses the suppression of TWIST1 caused by α-parvin loss.\",\n      \"method\": \"Co-immunoprecipitation (α-parvin-G3BP2 and G3BP2-TWIST1), ubiquitination assay, domain mutant rescue, siRNA knockdown, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for both complexes, ubiquitination assay, domain mutant rescue, epistasis; single lab\",\n      \"pmids\": [\"30804457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"G3BP2 regulates IκBα localization in endothelial cells; knockdown of G3BP2 reduces ox-LDL-induced inflammation via controlling IκBα localization, and G3bp2 knockout in ApoE-/- mice decreases atherosclerotic lesions with reduced pro-inflammatory cytokines.\",\n      \"method\": \"siRNA knockdown, Co-IP (G3BP2-IκBα), subcellular fractionation for IκBα localization, in vivo ApoE-/- mouse model\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for G3BP2-IκBα interaction, KD with IκBα localization readout, in vivo KD model; single lab\",\n      \"pmids\": [\"32919187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of G3BP2 in endothelial cells exposed to oscillatory shear stress increases YAP nucleocytoplasmic shuttling and phosphorylation, thereby diminishing OSS-induced inflammation. G3bp2 knockout in ApoE-/- mice decreases atherosclerotic lesions by protecting endothelial barrier function and reducing monocyte adhesion.\",\n      \"method\": \"siRNA/shRNA knockdown, partial ligation mouse model, RNA-seq, YAP localization/phosphorylation assays, in vivo G3bp2 Apoe double-knockout\",\n      \"journal\": \"Genes & Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined phenotype, YAP pathway placement via phosphorylation/localization; single lab\",\n      \"pmids\": [\"36157502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G3BP2 recruits lysosomal TSC2 to suppress mTORC1 under low-lactate stress; HDAC6 deacetylates TSC2 to sustain its stability and associates with G3BP2 to facilitate TSC2 recruitment, forming an HDAC6-G3BP2 complex that drives mTORC1 inhibition. HDAC6's microtubule retrograde transport activity promotes perinuclear mTOR distribution under stress.\",\n      \"method\": \"Co-immunoprecipitation (G3BP2-HDAC6-TSC2 complex), mTORC1 activity assays, HDAC6 deacetylation assay, live cell imaging of mTOR distribution\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for HDAC6-G3BP2-TSC2 complex, enzymatic deacetylation assay, pathway phenotype; single lab\",\n      \"pmids\": [\"36823378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cereblon (CRBN) can be directed by molecular glue degraders (MGDs) to ubiquitinate and degrade G3BP2 as a neosubstrate. The ternary complex structure reveals G3BP2 engages an unconventional binding site on the CRBN LON domain (not the canonical CULT domain G-loop), and CRBN mimics an endogenous binding partner of G3BP2 by exploiting a pre-existing PPI hotspot on G3BP2.\",\n      \"method\": \"Crystal/structural analysis of ternary complex, biochemical ubiquitination assay, proteomics\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination of ternary complex at defined resolution plus biochemical validation of degradation, novel binding mode established\",\n      \"pmids\": [\"41559416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"G3BPs (G3BP1 and G3BP2) and stress granules are necessary and sufficient to reinforce the integrated stress response translation program: they help prioritize translation of stress-resistant mRNAs enriched in SGs and suppress global cytosolic translation during stress, demonstrated using optogenetic tools and spike-normalized ribosome profiling.\",\n      \"method\": \"Optogenetic SG induction, spike-normalized ribosome profiling, G3BP1/2 double knockout, mRNA enrichment analysis in SGs\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ribosome profiling with optogenetic tools and KO in single lab; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"G3BP2 promotes ubiquitin-mediated degradation of STAT1; a lncRNA (LINC2781) directly binds G3BP2 and prevents this G3BP2-mediated STAT1 degradation through ubiquitination, thereby activating JAK-STAT signaling and antiviral ISG expression.\",\n      \"method\": \"Co-immunoprecipitation (G3BP2-STAT1 and LINC2781-G3BP2), ubiquitination assay, siRNA knockdown, ISG expression assay, in vivo mouse infection model\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating G3BP2-STAT1 interaction and lncRNA competition, ubiquitination assay; single lab\",\n      \"pmids\": [\"40626722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"G3BP2 acetylation at lysine 76 (K76), catalyzed by p300 and reversed by HDAC6, enhances G3BP2 binding to PABPC1 and PD-L1 mRNA, increasing PD-L1 mRNA stability and PD-L1 protein expression, thereby promoting immune evasion in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation (G3BP2-PABPC1), RNA immunoprecipitation (G3BP2-PD-L1 mRNA), acetylation site mutagenesis, p300/HDAC6 writer-eraser identification, mRNA stability assay, in vivo immunocompetent mouse models\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM site identified with writer (p300) and eraser (HDAC6), Co-IP and RIP for effector complex, in vivo validation; single lab\",\n      \"pmids\": [\"41906099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ROBO1 interacts with eIF3A and G3BP2 after irradiation, forming a hetero-complex that triggers lysosome-mediated eIF3A degradation; G3BP2 knockdown abrogates ROBO1's effect on eIF3A instability, placing G3BP2 as an essential component of this degradation complex.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry (complex identification), siRNA knockdown epistasis, lysosomal inhibitor experiments\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified complex, KD epistasis demonstrating G3BP2 requirement; single lab\",\n      \"pmids\": [\"40188129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EPS8L2 increases YBX1 phosphorylation by enhancing YBX1's interaction with S6K1; phosphorylated YBX1 translocates to the nucleus and initiates G3BP2 transcription, activating the MAPK signaling pathway to drive colorectal cancer proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (EPS8L2-YBX1-S6K1), YBX1 phosphorylation assay, nuclear translocation assay, G3BP2 promoter-reporter, MAPK pathway activation assay, in vivo AOM/DSS mouse model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, promoter reporter, in vivo model; single lab with multiple methods placing G3BP2 downstream of the EPS8L2-YBX1 axis\",\n      \"pmids\": [\"40783393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"G3BP2 suppresses p53 signaling in rheumatoid arthritis fibroblast-like synoviocytes (FLSs) by promoting p53 ubiquitination; G3BP2 silencing or compound C108 treatment reduces p53 ubiquitination, increases nuclear p53 levels, and suppresses RA-FLS migration and invasion. The p53 inhibitor PFT-α reverses the C108 inhibitory effect, confirming epistatic placement.\",\n      \"method\": \"siRNA knockdown, compound C108 treatment, ubiquitination assay for p53, RNA sequencing, p53 inhibitor epistasis, in vivo adjuvant-induced arthritis rat model\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay, epistasis via p53 inhibitor rescue, in vivo model; single lab\",\n      \"pmids\": [\"41338150\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"G3BP2 is a multifunctional RNA-binding protein and core stress granule scaffold that: (1) sequesters cytoplasmic binding partners (TWIST1, p53) to control their nuclear translocation in response to mechanical or hormonal signals; (2) stabilizes or destabilizes specific mRNA targets (SART3, HDGF, PD-L1, c-Myc) via direct mRNA binding, with post-translational modifications (arginine methylation by PRMT5, phosphorylation at Thr226/Thr227 by RIOK1/MAP4K4, acetylation at K76 by p300/HDAC6, deubiquitination by USP7) fine-tuning its activity; (3) facilitates stress granule assembly through NTF2-like domain-mediated homo- and heterodimerization and FGDF-motif interactions with partner proteins; (4) supports replication of multiple RNA viruses (alphaviruses, SARS-CoV-2) while being proteolytically targeted by viral proteases (FMDV Lpro) to disrupt SG-mediated antiviral defenses; and (5) inhibits Tau aggregation by masking the microtubule-binding region of Tau, serving as a natural defense in tauopathies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"G3BP2 is a multifunctional RNA-binding scaffold protein that nucleates stress granule (SG) assembly and couples cytoplasmic mRNA fate and protein sequestration to mechanical, hormonal, and stress signals [#1, #0]. Through its NTF2-like domain it forms homo- and hetero-multimers with G3BP1 and engages FGDF-motif partners, with the domain crystallizing as a homodimer that binds FGDF peptides via a hydrophobic surface [#11]; both G3BPs are required for efficient SG formation, and G3BP2 overexpression alone induces SGs without stress [#1]. As a cytoplasmic sequestering platform, G3BP2 retains TWIST1 under low matrix stiffness to restrain EMT and metastasis [#0], and drives RanBP2/TRIM25-dependent SUMOylation and nuclear export of p53 to suppress its tumor-suppressor activity downstream of androgen receptor induction [#5, #6]. G3BP2 additionally controls the stability and translation of specific transcripts—stabilizing SART3, HDGF, and PD-L1 mRNAs while degrading c-Myc mRNA—to influence stemness, migration, and immune evasion [#8, #18, #16, #19]. Its activity is tuned by a layered code of post-translational modifications: phosphorylation at Thr226/Thr227 by RIOK1 and MAP4K4, arginine methylation at R468 by PRMT5 (promoting USP7-mediated deubiquitination and stabilization), and K76 acetylation by p300 reversed by HDAC6 (enhancing PABPC1 and PD-L1 mRNA binding) [#15, #23, #20, #33]. In antiviral immunity G3BP2 supports SG-based defenses and is a target for viral antagonism: it associates with alphavirus replication proteins, is proteolytically cleaved by foot-and-mouth disease virus Lpro to disable SGs, and redundantly with G3BP1 restricts SARS-CoV-2 whose N protein disrupts the G3BP–SG axis [#4, #3, #13, #22]. G3BP2 also directly binds Tau, masking its microtubule-binding region to inhibit aggregation, and its loss elevates Tau pathology in human neurons [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first physical link between G3BP2 and viral RNA replication machinery, raising the question of whether host SG proteins are co-opted or antiviral during alphavirus infection.\",\n      \"evidence\": \"Affinity purification/MS of FLAG-tagged Sindbis virus nsP4 with functional depletion in infected cells\",\n      \"pmids\": [\"20392851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction identified by MS without direct binary binding validation\", \"Whether G3BP2 promotes or limits replication not cleanly resolved here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined G3BP2 as a core SG scaffold by showing it multimerizes with G3BP1 and is itself sufficient to induce SGs, identifying the molecular building block of granule assembly.\",\n      \"evidence\": \"Reciprocal Co-IP, single/double siRNA knockdown, overexpression, and SG immunofluorescence counting\",\n      \"pmids\": [\"23279204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of multimerization\", \"RNA targets within SGs not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected G3BP2 to signal-dependent regulation, identifying PKCα as a direct binding kinase and arginine methylation as a Wnt-responsive switch, indicating its activity is post-translationally controlled.\",\n      \"evidence\": \"RNase-resistant Co-IP, recombinant in vitro kinase assay, methyltransferase inhibition and methylation-deficient mutants with LRP6 phosphorylation readout\",\n      \"pmids\": [\"22536444\", \"22357953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKCα phosphorylation sites on G3BP2 not mapped\", \"Functional consequence of PKCα phosphorylation on SG dynamics unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed G3BP2 acts in translational control of antiviral ISG mRNAs and is a target of flaviviral subversion, framing it as both a host defense factor and a viral target.\",\n      \"evidence\": \"siRNA knockdown with polysome/translation assays and sfRNA RNA pulldown demonstrating direct binding\",\n      \"pmids\": [\"24992036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mRNA-binding determinants on G3BP2 not mapped\", \"Mechanism by which sfRNA sponging blocks translation not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined G3BP2 as a mechanotransducer that sequesters TWIST1 in the cytoplasm, answering how matrix stiffness gates EMT and metastasis.\",\n      \"evidence\": \"Co-IP, knockdown, live-cell imaging, and in vivo tumor models\",\n      \"pmids\": [\"25893917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor of stiffness that releases TWIST1 not identified\", \"Binding interface on G3BP2 for TWIST1 not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the structural basis of partner engagement by crystallizing the G3BP2 NTF2-like domain bound to an FGDF peptide, establishing the homodimeric module that underlies SG and viral protein interactions.\",\n      \"evidence\": \"X-ray crystallography of NTF2-like/FGDF complex at 2.75 Å\",\n      \"pmids\": [\"26410532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length protein architecture and RNA-binding domain not structurally defined\", \"How dimerization translates to granule condensation not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed G3BP2 in an androgen-receptor-driven oncogenic axis that exports p53, explaining how its overexpression inactivates a tumor suppressor in prostate cancer.\",\n      \"evidence\": \"ChIP for AR induction, Co-IP for G3BP2-RanBP2, fractionation/IF for p53 localization, xenografts\",\n      \"pmids\": [\"28692047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct G3BP2 contribution to SUMO-ligase activity not biochemically defined\", \"Generality beyond prostate cancer untested at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the mRNA-stabilizing role of G3BP2 to cancer stemness by linking it to SART3 mRNA and pluripotency factors.\",\n      \"evidence\": \"Chemical-probe (C108) target ID, mRNA stability assays, knockdown/overexpression with TIC readouts\",\n      \"pmids\": [\"28096337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct G3BP2-SART3 mRNA binding sites not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TRIM25 and USP10 as regulators of the G3BP2-p53 export axis and of G3BP2 stability, revealing how complex membership and deubiquitination sustain its oncogenic function.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, knockdown with p53 localization and growth phenotypes, xenografts\",\n      \"pmids\": [\"29379164\", \"29378906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP10 not identified\", \"Reciprocal validation of complexes limited to single labs\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that viral proteases directly disable G3BP2 to dismantle SG defenses, distinguishing scaffold cleavage from upstream stress kinase signaling.\",\n      \"evidence\": \"Recombinant chimeric virus, immunoblot for cleavage, SG assays, PKR/eIF2α phosphorylation controls, replicated in a second virus\",\n      \"pmids\": [\"30404792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cleavage site within G3BP2 not specified here\", \"Consequences for non-SG functions of G3BP2 untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed α-parvin gates the G3BP2-TWIST1 interaction and TWIST1 degradation, refining how upstream adhesion-linked factors control the mechanosensitive sequestration circuit.\",\n      \"evidence\": \"Co-IP of both complexes, ubiquitination assay, domain-mutant rescue, knockdown, in vivo tumor models\",\n      \"pmids\": [\"30804457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which α-parvin displaces TWIST1 not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked G3BP2 to inflammatory signaling by controlling IκBα localization and NF-κB activity in vascular and cardiac contexts, broadening its role beyond cancer and stress granules.\",\n      \"evidence\": \"Co-IP (G3BP2-IκBα), knockdown/overexpression, NF-κB reporters, fractionation, and ApoE-/- mouse models\",\n      \"pmids\": [\"28816235\", \"32919187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether G3BP2-IκBα binding directly alters IκBα degradation unresolved\", \"Tissue specificity of the effect not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the G3BP2 mRNA regulon to HDGF, PD-L1, and c-Myc, establishing it as a sequence-selective controller of transcript stability driving migration, immune evasion, and proliferation.\",\n      \"evidence\": \"RIP/RNA pulldown, mRNA stability and luciferase reporter assays, knockdown with rescue, in vivo tumor immunology\",\n      \"pmids\": [\"34782720\", \"33525064\", \"33476486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding motif distinguishing stabilized vs degraded targets unknown\", \"Each target characterized in a single tumor context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified MG53/TRIM72 as a factor that drives nuclear translocation of G3BP2 to block SG formation, positioning G3BP2 as an essential downstream effector of an anti-proliferative pathway.\",\n      \"evidence\": \"Co-IP with TRIM domain mapping, shRNA knockdown, live imaging, allograft/xenograft models\",\n      \"pmids\": [\"34521423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of forced nuclear import not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established phosphorylation by RIOK1 at Thr226 as an activating modification that amplifies G3BP2-driven p53 degradation and radioresistance, opening the post-translational regulatory layer.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay with site ID, ubiquitination assay, inhibition, in vivo tumor models\",\n      \"pmids\": [\"35589951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation mechanistically enhances p53 degradation not structurally resolved\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a PRMT5/USP7 arginine-methylation/deubiquitination axis stabilizing G3BP2 and a metabolic output via ACLY, integrating PTM control with lipogenesis and tumorigenesis.\",\n      \"evidence\": \"Co-IP, methylation site ID (R468me2), deubiquitination assays, PRMT5 inhibition, ACLY activity, in vivo models\",\n      \"pmids\": [\"36878903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How stabilized G3BP2 activates ACLY mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed G3BP2 directly binds Tau and masks its microtubule-binding region to inhibit aggregation, defining a protective function in tauopathy.\",\n      \"evidence\": \"Co-IP, in vitro aggregation assays, KO in human neurons and brain organoids, post-mortem tissue analysis\",\n      \"pmids\": [\"37385246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MTBR masking not resolved\", \"Whether SG assembly is required for the protective effect unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected G3BP2 to mTORC1 regulation and stress-dependent mRNA-translation reprogramming, showing it recruits TSC2 via an HDAC6 complex and partitions transcripts in SGs.\",\n      \"evidence\": \"Co-IP of HDAC6-G3BP2-TSC2 complex, mTORC1 activity and deacetylation assays, RIP, SG isolation\",\n      \"pmids\": [\"36823378\", \"39289547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolding role in TSC2 recruitment not separated\", \"Selectivity of mRNA partitioning into SGs not generalized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified MAP4K4 phosphorylation at Thr227 downstream of dipeptide import as a metabolic-stimulus-driven activating modification promoting metastasis.\",\n      \"evidence\": \"Co-IP of PEPT1-MAP4K4-G3BP2 axis, phospho-site ID, knockdown/overexpression, in vivo metastasis models\",\n      \"pmids\": [\"38639383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between Thr226 and Thr227 phosphorylation events not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Documented a nuclear PSF-G3BP2 complex stabilizing pre-mRNAs to support neuronal viability, extending G3BP2 function into the nucleus and neurodegeneration.\",\n      \"evidence\": \"Co-IP of nuclear complex, RNA-seq, qRT-PCR stability, aged mouse and human AD brain tissue\",\n      \"pmids\": [\"39155453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nuclear RNA targets not defined\", \"Causal link between reduced G3BP2 and AD pathology not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the redundancy and antiviral logic of G3BPs against SARS-CoV-2 and showed the N protein hijacks the G3BP2-TRIM25 interface to suppress interferon, clarifying virus-host competition at the SG scaffold.\",\n      \"evidence\": \"CRISPR double KO with viral replication assays, interaction-residue mapping, IFN production assays in infected cells\",\n      \"pmids\": [\"40733530\", \"36560452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative split of G3BP1 vs G3BP2 contributions not resolved\", \"Whether SG disruption alone explains the IFN phenotype unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated G3BP2 in ubiquitin/lysosome-mediated turnover of signaling proteins (STAT1, eIF3A), with lncRNAs competing for G3BP2 to tune antiviral and stress responses.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, MS complex ID, knockdown epistasis, ISG/lysosomal inhibitor experiments, in vivo infection\",\n      \"pmids\": [\"40626722\", \"40188129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether G3BP2 acts as adaptor or directly recruits ligases unresolved\", \"These degradation roles each rest on single studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined acetylation at K76 (p300 writer, HDAC6 eraser) as a modification that boosts PABPC1 and PD-L1 mRNA binding, completing a multi-PTM control map governing G3BP2 mRNA targeting and immune evasion.\",\n      \"evidence\": \"Co-IP, RIP, acetylation site mutagenesis, writer/eraser identification, mRNA stability, immunocompetent mouse models\",\n      \"pmids\": [\"41906099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between K76 acetylation and other PTMs not mapped\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided structural insight into G3BP2 degradability by showing cereblon molecular glues engage an unconventional LON-domain site exploiting a native PPI hotspot, establishing G3BP2 as a tractable degrader neosubstrate.\",\n      \"evidence\": \"Ternary complex structural analysis, biochemical ubiquitination assays, proteomics\",\n      \"pmids\": [\"41559416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous partner mimicked by CRBN not confirmed\", \"Functional consequence of induced G3BP2 degradation in cells not characterized here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the layered PTM code, partner sequestration, and selective mRNA stabilization/degradation are integrated to determine when G3BP2 protects (Tau, antiviral) versus promotes disease (oncogenic p53 export, immune evasion) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to specific mRNA target choice\", \"Structural basis for full-length G3BP2 RNA recognition undefined\", \"Determinants of nuclear vs cytoplasmic vs SG localization not mechanistically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 8, 16, 18, 19, 24, 33]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 26, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 18, 19, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 16, 22, 32, 33]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 9, 29, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10, 12, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 15, 20, 32, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 17, 27]}\n    ],\n    \"complexes\": [\"stress granule\", \"G3BP1-G3BP2 multimer\"],\n    \"partners\": [\"G3BP1\", \"TWIST1\", \"RanBP2\", \"TRIM25\", \"USP10\", \"HDAC6\", \"PABPC1\", \"TSC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}