{"gene":"CAPRIN1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2007,"finding":"Caprin-1 contains a conserved motif F(M/I/L)Q(D/E)Sx(I/L)D that directly binds the NTF2-like domain of G3BP-1; the carboxy-terminal RGG-rich region of Caprin-1 selectively binds c-Myc and cyclin D2 mRNAs (binding abolished by deletion of RGG motifs); overexpression of Caprin-1 induces eIF2α phosphorylation and stress granule formation via an RNA-binding-dependent mechanism; Caprin-1 colocalizes with G3BP-1 in cytoplasmic RNA granules associated with microtubules.","method":"Co-immunoprecipitation, GST pulldown, mutagenesis of RGG motifs, eIF2α phosphorylation assay, immunofluorescence/confocal microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (pulldown, mutagenesis, in-cell assays) in a single focused mechanistic study with domain-level resolution","pmids":["17210633"],"is_preprint":false},{"year":2005,"finding":"Caprin-1 is essential for normal G1-S cell cycle progression; conditional suppression of Caprin-1 in DT40 B cells slows proliferation due to prolongation of the G1 phase.","method":"Homologous recombination knockout in DT40 cells, conditional expression rescue, cell cycle analysis by flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean gene disruption with conditional rescue formally demonstrating requirement, replicated across multiple clonal approaches","pmids":["16177067"],"is_preprint":false},{"year":2016,"finding":"Caprin-1 and USP10 bind mutually exclusively to the NTF2-like domain of G3BP1; Caprin-1 binding promotes SG condensation while USP10 binding inhibits it. G3BP1-F33W, a mutant unable to bind Caprin-1 or USP10, still rescues SG formation in G3BP1/2 double-knockout cells, indicating Caprin-1/USP10 binding is not strictly required for G3BP1-dependent SG nucleation but modulates it. G3BP1 interacts with 40S ribosomal subunits through its RGG motif.","method":"G3BP1/2 double-knockout rescue experiments with G3BP1 mutants (S149E, F33W), co-immunoprecipitation, stress granule formation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic rescue with multiple point mutants, replicated across multiple stress conditions in a focused mechanistic study","pmids":["27022092"],"is_preprint":false},{"year":2015,"finding":"Caprin-1 directly interacts with PKR and regulates efficient PKR activation at stress granules; the G3BP1-Caprin-1-PKR complex mediates PKR activation and release of active PKR into the cytoplasm without requiring foreign dsRNA pattern recognition; this complex is important for antiviral activity against mengovirus.","method":"Direct binding assays (GST pulldown), co-immunoprecipitation, PKR activation assays, viral infection models, siRNA knockdown","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction assay combined with functional PKR activation readout and viral infection model, multiple orthogonal approaches","pmids":["25784705"],"is_preprint":false},{"year":2019,"finding":"Wild-type cytoplasmic SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin-1; prostate-cancer-associated SPOP mutants fail to degrade Caprin-1, causing its accumulation and aberrant enhancement of stress granule assembly in a Caprin-1-dependent manner.","method":"Yeast two-hybrid identification of SPOP-Caprin-1 interaction, co-immunoprecipitation, ubiquitination assays, protein stability assays, SG formation assays in cell lines and xenograft models","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction mapped by Y2H and Co-IP, ubiquitination biochemically demonstrated, functional consequence in multiple cancer cell lines and in vivo","pmids":["31771591"],"is_preprint":false},{"year":2019,"finding":"The C-terminal intrinsically disordered regions (IDRs) of FMRP and CAPRIN1 directly interact and co-phase separate; arginine-rich and aromatic-rich regions mediate IDR phase separation as determined by NMR; different serine/threonine phosphorylation of FMRP and tyrosine phosphorylation of CAPRIN1 control phase separation propensity with RNA, including condensate subcompartmentalization, and tune deadenylation and translation rates in vitro.","method":"NMR spectroscopy of condensed phase, in vitro phase separation assays, in vitro translation/deadenylation assays, phosphomimetic mutants","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural characterization combined with in vitro functional reconstitution (translation, deadenylation), multiple orthogonal methods in single rigorous study","pmids":["31439799"],"is_preprint":false},{"year":2014,"finding":"G3BP1, G3BP2, and CAPRIN1 are required for efficient translation of interferon-stimulated gene (ISG) mRNAs (including PKR and IFITM2); dengue virus sfRNA acts as a molecular sponge that binds all three proteins and inhibits their activity, blocking ISG mRNA translation.","method":"siRNA knockdown, polysome fractionation/translation assays, RNA-binding assays, viral infection models","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function combined with mRNA translation readout, mechanistic viral antagonism demonstrated, multiple RBPs tested in parallel","pmids":["24992036"],"is_preprint":false},{"year":2012,"finding":"JEV core protein directly binds Caprin-1; alanine scanning mutagenesis identified Lys97 and Arg98 in the JEV core protein α-helix as critical for Caprin-1 interaction; this interaction inhibits stress granule formation and is required for efficient viral propagation and virulence in mice.","method":"Affinity capture mass spectrometry, alanine scanning mutagenesis, stress granule formation assays, mutant virus infection models in vitro and in vivo","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — affinity purification MS identification, mutagenesis validation, functional viral propagation assay, and in vivo virulence model","pmids":["23097442"],"is_preprint":false},{"year":2012,"finding":"Caprin-1 physically interacts with FMRP in neuronal ribonucleoprotein complexes at the level of polysomes and in trafficking neuronal granules; Caprin-1 and FMRP share at least two common mRNA targets: CaMKIIα and Map1b mRNAs.","method":"Co-immunoprecipitation with monoclonal and chicken antibodies, sucrose gradient sedimentation (polysome analysis), immunofluorescence co-localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with two distinct antibodies plus polysome fractionation, single lab","pmids":["22737234"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the Caprin-1 dimerization domain (residues 132–251) reveals a novel all-α-helical fold that mediates homodimerization through a large hydrophobic interface; homodimerization creates a negatively charged concave surface. The FMRP-interacting sequence forms an integral α-helix within the dimer such that FMRP binding does not disrupt Caprin-1 homodimerization.","method":"X-ray crystallography (crystal structure determination), structural modelling of interaction surfaces","journal":"Acta crystallographica. Section D, Structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with domain-level resolution, single lab but rigorous structural method","pmids":["27303792"],"is_preprint":false},{"year":2021,"finding":"NMR studies of CAPRIN1 C-terminal IDR (residues 607–709) condensates identified specific side-chain and backbone interactions within the condensed phase; arginine-rich and aromatic-rich regions are critical for phase separation; ATP interactions can either enhance or reduce CAPRIN1 phase separation; O-GlcNAcylation reduces specific intra-condensate interactions relevant to cell cycle and stress responses.","method":"Solution NMR spectroscopy of condensed IDR states (multiple novel NMR experiments), mutagenesis, in vitro phase separation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution NMR of condensed phase combined with mutagenesis validation, multiple orthogonal NMR approaches","pmids":["34074792"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of G3BP1-NTF2 in complex with a Caprin-1 short linear motif (SLiM) reveals that Caprin-1 interacts with His-31 and His-62 within a third NTF2-binding site distinct from the USP10-binding sites; at acidic pH, G3BP1/Caprin-1 complex is less stable than G3BP1/USP10; condensate interior is approximately 0.5 pH units more acidic than cytosol.","method":"X-ray crystallography, nano-differential scanning fluorimetry, biochemical binding assays, ratiometric fluorescence pH measurement in cells","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biophysical binding assays and live-cell pH measurements, multiple orthogonal methods","pmids":["37161291"],"is_preprint":false},{"year":2022,"finding":"The C-terminal domain of Caprin-1 undergoes spontaneous liquid-liquid phase separation (LLPS) in vitro, while the N-terminal domain and the G3BP1-interacting motif (GIM) of Caprin-1 suppress LLPS of G3BP1; both Caprin-1 and USP10 GIMs bind the same hydrophobic pocket of G3BP1 NTF2L and both suppress G3BP1 LLPS. Caprin-1 thus promotes SG formation predominantly via its C-terminal domain-driven LLPS, not through GIM-G3BP1 interaction.","method":"Crystal structure of G3BP1-NTF2L:Caprin-1 GIM complex, in vitro LLPS assays with isolated domains, domain deletion/rescue experiments in cells with endogenous Caprin-1 knockout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro reconstitution of LLPS, and cellular rescue with domain mutants, multiple orthogonal methods","pmids":["36279435"],"is_preprint":false},{"year":2017,"finding":"RNG105/Caprin-1 deletion in mice impairs the asymmetric somato-dendritic localization of mRNAs encoding regulators of AMPAR surface expression, leading to attenuated homeostatic AMPAR scaling in dendrites, reduced synaptic strength and structural plasticity, and severe defects in long-term spatial and contextual memory formation.","method":"Conditional mouse knockout, genome-wide mRNA distribution profiling (in situ hybridization/sequencing), synaptic electrophysiology, behavioural memory tasks","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO with genome-wide mRNA localization profiling, electrophysiology, and behavioural readouts, multiple orthogonal methods","pmids":["29157358"],"is_preprint":false},{"year":2010,"finding":"RNG105 knockout in mice reduces dendritic localization of Na+/K+ ATPase subunit isoform mRNAs (α3, FXYD1, FXYD6, FXYD7), causing loss of NKA function specifically in dendrites without affecting somatic NKA, and impairing synapse formation and maintenance.","method":"Mouse knockout, in situ hybridization for mRNA localization, NKA activity assays in subcellular fractions, synapse quantification","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO with mRNA localization and functional enzymatic assays, replicated across multiple NKA subunit mRNAs","pmids":["20861386"],"is_preprint":false},{"year":2022,"finding":"CAPRIN1 associates with thousands of RNA transcripts in embryonic stem cells and promotes their degradation through interaction with the ribonuclease XRN2; upon early ESC differentiation, XRN2 localizes to the nucleus and colocalizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner.","method":"CAPRIN1 knockout in mouse ESCs, RIP-seq, SLAM-seq, co-immunoprecipitation/interactome identification of XRN2, fluorescent protein library screen, immunofluorescence","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO combined with RIP-seq, SLAM-seq, and interactome identification, multiple orthogonal methods","pmids":["36495875"],"is_preprint":false},{"year":2021,"finding":"Upon glutamine deprivation, lncRNA GIRGL drives formation of a complex between CAPRIN1 dimers and GLS1 mRNA, promoting liquid-liquid phase separation of CAPRIN1 and stress granule formation, which suppresses GLS1 mRNA translation.","method":"RNA pulldown, co-immunoprecipitation, in vitro phase separation assays, CAPRIN1 knockdown with GLS1 translation readout, lncRNA overexpression/knockdown","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown and LLPS reconstitution with functional translation readout, single lab","pmids":["33762340"],"is_preprint":false},{"year":2015,"finding":"Tylophorine directly binds Caprin-1 and enhances recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA into a ribonucleoprotein complex that is sequestered to polysomal fractions, repressing translation of associated mRNAs; Caprin-1-depleted cells are more resistant to tylophorine and show decreased RNP complex formation.","method":"Biotinylated tylophorine pulldown/affinity capture, co-immunoprecipitation, polysome fractionation, Caprin-1 siRNA knockdown, gene expression profiling","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity capture identifies direct binding, functional translation readout and loss-of-function confirmation, single lab","pmids":["25669982"],"is_preprint":false},{"year":2013,"finding":"Caprin-1 directly interacts with Cyr61; ectopic Caprin-1 expression leads to formation of stress granules containing Caprin-1 and Cyr61, confers resistance to cisplatin-induced apoptosis, and constitutively activates Akt and ERK1/2 signaling.","method":"Co-immunoprecipitation, confocal microscopy, apoptosis assays, western blotting for Akt/ERK1/2 phosphorylation, in vivo xenograft model","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction plus functional signaling readout and in vivo model, single lab","pmids":["23528710"],"is_preprint":false},{"year":2017,"finding":"DDX3X physically interacts and co-localizes with Caprin-1 and poly(A)-binding protein 1 (PABP1) at the leading edge of spreading/migrating fibroblasts; depletion of DDX3X decreases cell motility, linking the DDX3X-Caprin-1 interaction to cell migration.","method":"Co-immunoprecipitation, immunofluorescence co-localization, DDX3X depletion with motility assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and localization data with functional depletion phenotype, single lab, two orthogonal approaches","pmids":["28733330"],"is_preprint":false},{"year":2022,"finding":"The CAPRIN1 P512L mutation causes aberrant protein aggregation; overexpressed CAPRIN1-P512L forms insoluble ubiquitinated aggregates that sequester neurodegenerative disease-associated proteins (ATXN2, GEMIN5, SNRNP200, SNCA); P512L mutation in iPSC-derived cortical neurons reduces neuronal activity and alters stress granule dynamics; RNA strongly enhances CAPRIN1-P512L aggregation in vitro.","method":"Patient exome sequencing, isogenic iPSC neurons, overexpression/solubility assays, co-immunoprecipitation, nano-DSF, stress granule formation assays, MEA electrophysiology","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic human neuronal model with multiple orthogonal assays (biochemical aggregation, co-IP, electrophysiology, in vitro RNA-driven aggregation)","pmids":["36136249"],"is_preprint":false},{"year":2023,"finding":"CAPRIN1 haploinsufficiency in human iPSC-derived neurons causes reduced neuronal processes, disrupted neuronal organization, increased neurodegeneration, altered mRNA translation (consistent with translational inhibitor function), impaired calcium signaling, increased oxidative stress, and reduced neuronal network activity.","method":"CRISPR-Cas9 haploinsufficiency iPSC model, differentiation into neuronal progenitors and cortical neurons, micro-electrode arrays, calcium imaging, oxidative stress assays, translation assays","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic human neuronal model with multiple orthogonal functional readouts, CRISPR-controlled genetic manipulation","pmids":["35979925"],"is_preprint":false},{"year":2023,"finding":"CAPRIN1 interacts with ATG16L1 and mediates LC3 targeting of murine norovirus replication complexes; IFN-gamma-mediated control of MNV replication is dependent on CAPRIN1.","method":"Co-immunoprecipitation, CAPRIN1 knockdown/knockout, viral replication assays, IFN-gamma treatment","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction and CAPRIN1 loss-of-function with viral replication readout, single lab","pmids":["37052473"],"is_preprint":false},{"year":2022,"finding":"WDR45 forms gel-like condensates via its WD5 domain that phase separate with Caprin-1; WDR45 competitively displaces G3BP1 from Caprin-1 to promote stress granule disassembly; BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly.","method":"Co-immunoprecipitation, in vitro phase separation assays, competitive binding assays, BPAN patient iPSC-derived neurons, SG dynamics assays, domain deletion mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cellular methods, disease mutation validation in patient-derived neurons","pmids":["40473629"],"is_preprint":false},{"year":2025,"finding":"CAPRIN1 selectively binds STAT1 mRNA via the 5'UTR G-quadruplex (rG4) structure, stabilizes the rG4 conformation, halts ribosomal scanning, and suppresses STAT1 protein production; this suppresses interferon signaling; HBV polymerase functions as a transcription factor that upregulates CAPRIN1 expression during HBV infection.","method":"Ribonucleoprotein immunoprecipitation-MS, EMSA, luciferase reporter assays, ribosome profiling, circular dichroism, CAPRIN1 knockdown/re-expression in vitro and in vivo","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (RIP-MS, EMSA, ribosome profiling, CD) combined with loss-of-function and functional IFN readout","pmids":["41951358"],"is_preprint":false},{"year":2026,"finding":"CAPRIN1 interacts with NCOA4 mRNA via its RGG domain and recruits NCOA4 mRNA into stress granules, repressing NCOA4 translation and blunting sorafenib-induced ferroptosis in hepatocellular carcinoma; genetic disruption of CAPRIN1 restores NCOA4 expression and resensitizes resistant tumors to sorafenib.","method":"Co-immunoprecipitation, RNA immunoprecipitation, RGG domain mutagenesis, CAPRIN1 knockout, ferroptosis assays, in vivo xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP with domain mutagenesis and functional ferroptosis readout in vitro and in vivo, single lab","pmids":["41896589"],"is_preprint":false},{"year":2025,"finding":"CAPRIN1 regulates m6A modification of RIG-I mRNA through direct interaction with METTL3, influencing downstream interferon-associated gene networks and modulating M. tuberculosis infection; these processes predominantly occur within cellular stress granules.","method":"m6A RIP assay, co-immunoprecipitation (CAPRIN1-METTL3 interaction), CAPRIN1 knockdown, RIG-I m6A quantification, infection models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — m6A-RIP and Co-IP with functional infection readout, single lab, mechanistic link to METTL3 established biochemically","pmids":["41198861"],"is_preprint":false},{"year":2025,"finding":"Caprin-1 binding to NMDA receptor 3B mRNA stabilizes it (demonstrated by circ288 binding to Caprin-1 and inhibiting its degradation, raising NMDAR3B mRNA levels); neuron-specific caprin-1 knockout mice lose the protective effect of circ288 overexpression, placing Caprin-1 upstream of NMDAR3B mRNA regulation.","method":"Neuron-specific Caprin-1 conditional knockout (CaMK2α-Cre:Caprin1f/f), AAV-mediated overexpression, mRNA stability assays, in vitro epilepsy model, RNA binding assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO epistasis places Caprin-1 upstream of NMDAR3B regulation, but mechanism is partially inferred from circRNA interaction context, single lab","pmids":["39962265"],"is_preprint":false},{"year":2023,"finding":"Caprin-1 interacts with both ULK1 and STK38 in pancreatic cancer cells and manipulates ULK1 phosphorylation to activate autophagy, promoting pro-tumorigenic phenotypes.","method":"Co-immunoprecipitation, ULK1 phosphorylation assays, CAPRIN1 knockdown, autophagy flux assays","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP binding and phosphorylation assay from a single lab with limited mechanistic follow-up on the ULK1 activation mechanism","pmids":["38082307"],"is_preprint":false},{"year":2025,"finding":"CAPRIN1 binds and stabilizes YY1 mRNA; YY1 then transcriptionally activates HSP90AA1; HSP90α binds and stabilizes IDH1 protein, protecting it from degradation; this cascade (CAPRIN1→YY1 mRNA stabilization→HSP90α→IDH1 stabilization) suppresses ferroptosis and promotes cisplatin resistance in cervical cancer.","method":"RNA immunoprecipitation, RNA pulldown, actinomycin D mRNA stability assay, dual-luciferase/ChIP assay for YY1-HSP90AA1, co-IP for HSP90α-IDH1, CAPRIN1 knockdown + IDH1 rescue, xenograft model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pulldown for Caprin-1 mRNA binding, multiple epistasis steps validated biochemically, rescue experiments confirm pathway, single lab","pmids":["42114793"],"is_preprint":false},{"year":2025,"finding":"Caprin-1 FMRP-interacting helix is part of an integral α-helix in the HR1 homodimeric structure (Caprin-2 comparison); HR1 dimerization is an evolutionarily conserved feature of the caprin family, and different molecular surface properties between Caprin-1 and Caprin-2 dimers likely dictate specificity for distinct protein partners.","method":"X-ray crystallography of Caprin-2 HR1 fragment, structural comparison with Caprin-1 structure","journal":"Journal of biomolecular structure & dynamics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of Caprin-2 with structural inference for Caprin-1, single lab, functional validation limited","pmids":["30304999"],"is_preprint":false}],"current_model":"CAPRIN1 is an RNA-binding protein that functions as a core scaffold of stress granules and neuronal RNA granules: it binds G3BP1 via a conserved SLiM (promoting stress granule condensation through its C-terminal IDR-driven phase separation), directly interacts with FMRP and PKR to form an RNP complex that regulates mRNA translation and innate immune PKR activation, selectively binds c-Myc and cyclin D2 mRNAs through its RGG motifs to control their translation, mediates dendritic mRNA localization essential for synaptic plasticity and long-term memory, undergoes phosphorylation- and O-GlcNAcylation-regulated liquid-liquid phase separation driven by arginine-aromatic interactions in its C-terminal IDR, is subject to SPOP-mediated ubiquitin-dependent degradation, promotes RNA degradation via XRN2 during stem cell differentiation, and suppresses STAT1 translation by stabilizing an rG4 structure in the STAT1 5'UTR to dampen interferon signaling."},"narrative":{"mechanistic_narrative":"CAPRIN1 is an RNA-binding protein that serves as a core scaffold of cytoplasmic RNA granules, coupling mRNA fate control to stress and developmental signaling [PMID:17210633, PMID:27022092]. It engages G3BP1 through a conserved short linear motif (FxQDSxxD) that docks onto a distinct site on the G3BP1 NTF2-like domain involving His-31/His-62, binding mutually exclusively with USP10 [PMID:17210633, PMID:27022092, PMID:37161291]; while this interaction modulates G3BP1, CAPRIN1 drives stress granule condensation chiefly through liquid-liquid phase separation of its C-terminal intrinsically disordered region, governed by arginine-aromatic side-chain interactions and tuned by tyrosine phosphorylation, O-GlcNAcylation, and ATP [PMID:31439799, PMID:34074792, PMID:36279435]. CAPRIN1 homodimerizes via an all-α-helical HR1 domain that also forms the FMRP-interacting interface, allowing it to co-phase-separate with FMRP and modulate deadenylation and translation [PMID:31439799, PMID:27303792]. Through its C-terminal RGG motifs CAPRIN1 selectively binds target transcripts including c-Myc and cyclin D2 mRNAs to control their translation, consistent with its requirement for G1-S cell cycle progression [PMID:17210633, PMID:16177067]. CAPRIN1 also forms an RNP complex with PKR that supports stress-granule-dependent PKR activation and antiviral defense, and is required with G3BP for efficient translation of interferon-stimulated mRNAs, making it a frequent target of viral antagonists [PMID:25784705, PMID:24992036, PMID:23097442]. In neurons, CAPRIN1 (RNG105) directs asymmetric dendritic localization of mRNAs encoding AMPAR regulators and Na+/K+-ATPase subunits, supporting synapse formation, homeostatic plasticity, and long-term memory [PMID:29157358, PMID:20861386]. CAPRIN1 protein abundance is set by SPOP-mediated ubiquitin-dependent degradation, and CAPRIN1 mutations and haploinsufficiency cause aberrant aggregation, disrupted stress granule dynamics, and neurodegenerative phenotypes in patient-derived neurons [PMID:31771591, PMID:36136249, PMID:35979925].","teleology":[{"year":2005,"claim":"Establishing that CAPRIN1 has an essential cellular function, before any molecular activity was known, motivated mechanistic dissection of how it controls proliferation.","evidence":"Conditional homologous-recombination knockout in DT40 B cells with rescue and cell-cycle flow cytometry","pmids":["16177067"],"confidence":"High","gaps":["Did not identify the molecular activity underlying the G1 prolongation","No RNA targets linked to the proliferation phenotype at this stage"]},{"year":2007,"claim":"Defined CAPRIN1 as a sequence-specific RNA-binding protein and G3BP1 partner, establishing the molecular basis for its role in stress granules and translational control of growth genes.","evidence":"Co-IP, GST pulldown, RGG-motif mutagenesis, eIF2α phosphorylation and stress granule assays with confocal imaging","pmids":["17210633"],"confidence":"High","gaps":["Direct vs indirect mode of c-Myc/cyclin D2 translational control not resolved","Structural basis of the G3BP1 motif interaction not defined"]},{"year":2012,"claim":"Connected CAPRIN1 to neuronal mRNA transport and to viral antagonism, showing it operates in both FMRP-containing neuronal RNP granules and as a host antiviral target.","evidence":"Reciprocal Co-IP and polysome fractionation for FMRP (neurons); affinity-MS and mutagenesis for JEV core protein binding with in vivo virulence","pmids":["22737234","23097442"],"confidence":"Medium","gaps":["FMRP/CAPRIN1 shared-target work limited to two mRNAs and a single lab","Functional consequence of FMRP co-association on translation not measured directly here"]},{"year":2015,"claim":"Showed CAPRIN1 organizes innate immune signaling complexes, demonstrating it directly binds PKR and is required for ISG mRNA translation, positioning stress granules as antiviral signaling platforms.","evidence":"GST pulldown, Co-IP, PKR activation assays, polysome translation assays, siRNA, viral infection models","pmids":["25784705","24992036"],"confidence":"High","gaps":["How CAPRIN1 mechanistically promotes ISG-mRNA translation not resolved","Stoichiometry of the G3BP1-CAPRIN1-PKR complex undefined"]},{"year":2016,"claim":"Resolved the architecture and competitive logic of CAPRIN1 within stress granules, showing CAPRIN1 and USP10 bind G3BP1 mutually exclusively to oppositely tune condensation, and that CAPRIN1 self-associates through a novel helical dimerization fold.","evidence":"G3BP1/2 double-KO rescue with point mutants and Co-IP; X-ray crystallography of the CAPRIN1 dimerization domain","pmids":["27022092","27303792"],"confidence":"High","gaps":["CAPRIN1/USP10 binding shown not strictly required for SG nucleation, leaving its precise contribution unclear","Functional role of the negatively charged dimer surface not tested"]},{"year":2017,"claim":"Demonstrated the physiological output of CAPRIN1-dependent mRNA localization, linking dendritic transport of plasticity-related mRNAs to synaptic strength, homeostatic scaling, and memory.","evidence":"Conditional mouse KO with genome-wide mRNA distribution profiling, electrophysiology, and behavioural memory tasks; earlier KO defining NKA-subunit mRNA dependence","pmids":["29157358","20861386"],"confidence":"High","gaps":["Direct mRNA-binding selectivity within dendritic transport granules not fully mapped","Whether phase separation drives dendritic localization in vivo untested"]},{"year":2019,"claim":"Identified the post-translational control of CAPRIN1 abundance and reconstituted its phase behavior with FMRP, establishing how condensate composition and phosphorylation tune translation and deadenylation.","evidence":"Y2H/Co-IP/ubiquitination assays for SPOP; NMR of FMRP-CAPRIN1 condensates with in vitro translation/deadenylation and phosphomimetics","pmids":["31771591","31439799"],"confidence":"High","gaps":["In vivo significance of SPOP-CAPRIN1 degradation outside cancer contexts unclear","Kinases setting CAPRIN1 tyrosine phosphorylation in cells not identified"]},{"year":2022,"claim":"Established at atomic and biophysical resolution how CAPRIN1 drives stress granule formation, showing the C-terminal IDR (not the G3BP1 motif) provides the phase-separating activity and defining the G3BP1-binding site and its pH dependence.","evidence":"Crystal structures of G3BP1-NTF2L:CAPRIN1 GIM, in vitro LLPS reconstitution with isolated domains, nanoDSF, and live-cell pH measurement","pmids":["36279435","37161291","34074792"],"confidence":"High","gaps":["Quantitative contribution of GIM binding vs IDR LLPS to granules in vivo not fully separated","Physiological triggers of the pH-dependent partner switch unclear"]},{"year":2022,"claim":"Linked CAPRIN1 dysfunction to human neurodegeneration, showing a point mutation and haploinsufficiency cause aberrant aggregation, altered stress granule dynamics, and impaired neuronal activity.","evidence":"Patient exome sequencing with isogenic iPSC-derived neurons, solubility/aggregation assays, nanoDSF, MEA electrophysiology, CRISPR haploinsufficiency model","pmids":["36136249","35979925"],"confidence":"High","gaps":["Mechanism connecting aggregation to specific neuronal deficits incompletely defined","Whether loss-of-function and gain-of-toxicity contribute differently not resolved"]},{"year":2022,"claim":"Identified CAPRIN1 as a regulated node in stress granule disassembly and degradative pathways, partnering with WDR45 and XRN2.","evidence":"Co-IP, in vitro phase separation/competition assays, BPAN patient iPSC neurons (WDR45); KO with RIP-seq/SLAM-seq and interactome (XRN2)","pmids":["40473629","36495875"],"confidence":"High","gaps":["How WDR45 displacement is triggered physiologically not defined","Selectivity rules for CAPRIN1/XRN2-targeted transcripts in ESCs unclear"]},{"year":2025,"claim":"Extended CAPRIN1 to structured-RNA recognition and disease-context translational control, showing it stabilizes a STAT1 5'UTR rG4 to dampen interferon signaling and acts in multiple cancer and infection programs.","evidence":"RIP-MS, EMSA, ribosome profiling, CD for STAT1 rG4; RIP/RGG mutagenesis and functional readouts for NCOA4, METTL3/RIG-I, NMDAR3B, and YY1 axes","pmids":["41951358","41896589","41198861","39962265","42114793"],"confidence":"Medium","gaps":["Most downstream axes rest on single-lab studies","General rules distinguishing CAPRIN1-mediated stabilization from degradation/repression of bound transcripts not unified"]},{"year":null,"claim":"How CAPRIN1's modular activities — RGG-mediated transcript selection, IDR phase separation, dimerization, and post-translational modification — are integrated to specify which mRNAs are localized, stabilized, or repressed in a given context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking condensate state to transcript-specific fate","Context-dependent switch between translational repression and mRNA stabilization undefined","Physiological signals controlling CAPRIN1 PTMs in vivo unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,15,24,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,11,12]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,5,24]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,15,24]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6,24,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,14,21,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,0]}],"complexes":["stress granule","G3BP1-CAPRIN1-PKR complex","FMRP-CAPRIN1 ribonucleoprotein granule"],"partners":["G3BP1","FMRP","PKR","USP10","XRN2","WDR45","SPOP","DDX3X"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14444","full_name":"Caprin-1","aliases":["Cell cycle-associated protein 1","Cytoplasmic activation- and proliferation-associated protein 1","GPI-anchored membrane protein 1","GPI-anchored protein p137","GPI-p137","p137GPI","Membrane component chromosome 11 surface marker 1","RNA granule protein 105"],"length_aa":709,"mass_kda":78.4,"function":"mRNA-binding protein that acts as a regulator of mRNAs transport, translation and/or stability, and which is involved in neurogenesis, synaptic plasticity in neurons and cell proliferation and migration in multiple cell types (PubMed:17210633, PubMed:31439799, PubMed:35979925). Plays an essential role in cytoplasmic stress granule formation (PubMed:35977029). Acts as an mRNA regulator by mediating formation of some phase-separated membraneless compartment: undergoes liquid-liquid phase separation upon binding to target mRNAs, leading to assemble mRNAs into cytoplasmic ribonucleoprotein granules that concentrate mRNAs with associated regulatory factors (PubMed:31439799, PubMed:32302570, PubMed:32302571, PubMed:32302572, PubMed:34074792, PubMed:36040869, PubMed:36279435). Undergoes liquid-liquid phase separation following phosphorylation and interaction with FMR1, promoting formation of cytoplasmic ribonucleoprotein granules that concentrate mRNAs with factors that inhibit translation and mediate deadenylation of target mRNAs (PubMed:31439799). In these cytoplasmic ribonucleoprotein granules, CAPRIN1 mediates recruitment of CNOT7 deadenylase, leading to mRNA deadenylation and degradation (PubMed:31439799). Binds directly and selectively to MYC and CCND2 mRNAs (PubMed:17210633). In neuronal cells, directly binds to several mRNAs associated with RNA granules, including BDNF, CAMK2A, CREB1, MAP2, NTRK2 mRNAs, as well as to GRIN1 and KPNB1 mRNAs, but not to rRNAs (PubMed:17210633)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q14444/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAPRIN1","classification":"Not 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WITH LANGUAGE IMPAIRMENT, AUTISM, AND ATTENTION DEFICIT-HYPERACTIVITY DISORDER; NEDLAAD","url":"https://www.omim.org/entry/620782"},{"mim_id":"620636","title":"NEURODEGENERATION, CHILDHOOD-ONSET, WITH CEREBELLAR ATAXIA AND COGNITIVE DECLINE; CONDCAC","url":"https://www.omim.org/entry/620636"},{"mim_id":"615857","title":"2-OXOGLUTARATE- AND IRON-DEPENDENT OXYGENASE DOMAIN-CONTAINING PROTEIN 1; OGFOD1","url":"https://www.omim.org/entry/615857"},{"mim_id":"609704","title":"MICRO RNA 16-1; MIR16-1","url":"https://www.omim.org/entry/609704"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAPRIN1"},"hgnc":{"alias_symbol":["caprin-1","RNG105"],"prev_symbol":["M11S1","GPIAP1"]},"alphafold":{"accession":"Q14444","domains":[{"cath_id":"-","chopping":"160-246","consensus_level":"medium","plddt":95.757,"start":160,"end":246},{"cath_id":"1.10.287","chopping":"44-138","consensus_level":"medium","plddt":94.2922,"start":44,"end":138}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14444","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14444-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14444-F1-predicted_aligned_error_v6.png","plddt_mean":57.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAPRIN1","jax_strain_url":"https://www.jax.org/strain/search?query=CAPRIN1"},"sequence":{"accession":"Q14444","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14444.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14444/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14444"}},"corpus_meta":[{"pmid":"27022092","id":"PMC_27022092","title":"G3BP-Caprin1-USP10 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the NTF2-like domain of G3BP-1; the carboxy-terminal RGG-rich region of Caprin-1 selectively binds c-Myc and cyclin D2 mRNAs (binding abolished by deletion of RGG motifs); overexpression of Caprin-1 induces eIF2α phosphorylation and stress granule formation via an RNA-binding-dependent mechanism; Caprin-1 colocalizes with G3BP-1 in cytoplasmic RNA granules associated with microtubules.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, mutagenesis of RGG motifs, eIF2α phosphorylation assay, immunofluorescence/confocal microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (pulldown, mutagenesis, in-cell assays) in a single focused mechanistic study with domain-level resolution\",\n      \"pmids\": [\"17210633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Caprin-1 is essential for normal G1-S cell cycle progression; conditional suppression of Caprin-1 in DT40 B cells slows proliferation due to prolongation of the G1 phase.\",\n      \"method\": \"Homologous recombination knockout in DT40 cells, conditional expression rescue, cell cycle analysis by flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean gene disruption with conditional rescue formally demonstrating requirement, replicated across multiple clonal approaches\",\n      \"pmids\": [\"16177067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Caprin-1 and USP10 bind mutually exclusively to the NTF2-like domain of G3BP1; Caprin-1 binding promotes SG condensation while USP10 binding inhibits it. G3BP1-F33W, a mutant unable to bind Caprin-1 or USP10, still rescues SG formation in G3BP1/2 double-knockout cells, indicating Caprin-1/USP10 binding is not strictly required for G3BP1-dependent SG nucleation but modulates it. G3BP1 interacts with 40S ribosomal subunits through its RGG motif.\",\n      \"method\": \"G3BP1/2 double-knockout rescue experiments with G3BP1 mutants (S149E, F33W), co-immunoprecipitation, stress granule formation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic rescue with multiple point mutants, replicated across multiple stress conditions in a focused mechanistic study\",\n      \"pmids\": [\"27022092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Caprin-1 directly interacts with PKR and regulates efficient PKR activation at stress granules; the G3BP1-Caprin-1-PKR complex mediates PKR activation and release of active PKR into the cytoplasm without requiring foreign dsRNA pattern recognition; this complex is important for antiviral activity against mengovirus.\",\n      \"method\": \"Direct binding assays (GST pulldown), co-immunoprecipitation, PKR activation assays, viral infection models, siRNA knockdown\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction assay combined with functional PKR activation readout and viral infection model, multiple orthogonal approaches\",\n      \"pmids\": [\"25784705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wild-type cytoplasmic SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin-1; prostate-cancer-associated SPOP mutants fail to degrade Caprin-1, causing its accumulation and aberrant enhancement of stress granule assembly in a Caprin-1-dependent manner.\",\n      \"method\": \"Yeast two-hybrid identification of SPOP-Caprin-1 interaction, co-immunoprecipitation, ubiquitination assays, protein stability assays, SG formation assays in cell lines and xenograft models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction mapped by Y2H and Co-IP, ubiquitination biochemically demonstrated, functional consequence in multiple cancer cell lines and in vivo\",\n      \"pmids\": [\"31771591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The C-terminal intrinsically disordered regions (IDRs) of FMRP and CAPRIN1 directly interact and co-phase separate; arginine-rich and aromatic-rich regions mediate IDR phase separation as determined by NMR; different serine/threonine phosphorylation of FMRP and tyrosine phosphorylation of CAPRIN1 control phase separation propensity with RNA, including condensate subcompartmentalization, and tune deadenylation and translation rates in vitro.\",\n      \"method\": \"NMR spectroscopy of condensed phase, in vitro phase separation assays, in vitro translation/deadenylation assays, phosphomimetic mutants\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural characterization combined with in vitro functional reconstitution (translation, deadenylation), multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31439799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"G3BP1, G3BP2, and CAPRIN1 are required for efficient translation of interferon-stimulated gene (ISG) mRNAs (including PKR and IFITM2); dengue virus sfRNA acts as a molecular sponge that binds all three proteins and inhibits their activity, blocking ISG mRNA translation.\",\n      \"method\": \"siRNA knockdown, polysome fractionation/translation assays, RNA-binding assays, viral infection models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function combined with mRNA translation readout, mechanistic viral antagonism demonstrated, multiple RBPs tested in parallel\",\n      \"pmids\": [\"24992036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JEV core protein directly binds Caprin-1; alanine scanning mutagenesis identified Lys97 and Arg98 in the JEV core protein α-helix as critical for Caprin-1 interaction; this interaction inhibits stress granule formation and is required for efficient viral propagation and virulence in mice.\",\n      \"method\": \"Affinity capture mass spectrometry, alanine scanning mutagenesis, stress granule formation assays, mutant virus infection models in vitro and in vivo\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — affinity purification MS identification, mutagenesis validation, functional viral propagation assay, and in vivo virulence model\",\n      \"pmids\": [\"23097442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Caprin-1 physically interacts with FMRP in neuronal ribonucleoprotein complexes at the level of polysomes and in trafficking neuronal granules; Caprin-1 and FMRP share at least two common mRNA targets: CaMKIIα and Map1b mRNAs.\",\n      \"method\": \"Co-immunoprecipitation with monoclonal and chicken antibodies, sucrose gradient sedimentation (polysome analysis), immunofluorescence co-localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with two distinct antibodies plus polysome fractionation, single lab\",\n      \"pmids\": [\"22737234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the Caprin-1 dimerization domain (residues 132–251) reveals a novel all-α-helical fold that mediates homodimerization through a large hydrophobic interface; homodimerization creates a negatively charged concave surface. The FMRP-interacting sequence forms an integral α-helix within the dimer such that FMRP binding does not disrupt Caprin-1 homodimerization.\",\n      \"method\": \"X-ray crystallography (crystal structure determination), structural modelling of interaction surfaces\",\n      \"journal\": \"Acta crystallographica. Section D, Structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with domain-level resolution, single lab but rigorous structural method\",\n      \"pmids\": [\"27303792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMR studies of CAPRIN1 C-terminal IDR (residues 607–709) condensates identified specific side-chain and backbone interactions within the condensed phase; arginine-rich and aromatic-rich regions are critical for phase separation; ATP interactions can either enhance or reduce CAPRIN1 phase separation; O-GlcNAcylation reduces specific intra-condensate interactions relevant to cell cycle and stress responses.\",\n      \"method\": \"Solution NMR spectroscopy of condensed IDR states (multiple novel NMR experiments), mutagenesis, in vitro phase separation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution NMR of condensed phase combined with mutagenesis validation, multiple orthogonal NMR approaches\",\n      \"pmids\": [\"34074792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of G3BP1-NTF2 in complex with a Caprin-1 short linear motif (SLiM) reveals that Caprin-1 interacts with His-31 and His-62 within a third NTF2-binding site distinct from the USP10-binding sites; at acidic pH, G3BP1/Caprin-1 complex is less stable than G3BP1/USP10; condensate interior is approximately 0.5 pH units more acidic than cytosol.\",\n      \"method\": \"X-ray crystallography, nano-differential scanning fluorimetry, biochemical binding assays, ratiometric fluorescence pH measurement in cells\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biophysical binding assays and live-cell pH measurements, multiple orthogonal methods\",\n      \"pmids\": [\"37161291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminal domain of Caprin-1 undergoes spontaneous liquid-liquid phase separation (LLPS) in vitro, while the N-terminal domain and the G3BP1-interacting motif (GIM) of Caprin-1 suppress LLPS of G3BP1; both Caprin-1 and USP10 GIMs bind the same hydrophobic pocket of G3BP1 NTF2L and both suppress G3BP1 LLPS. Caprin-1 thus promotes SG formation predominantly via its C-terminal domain-driven LLPS, not through GIM-G3BP1 interaction.\",\n      \"method\": \"Crystal structure of G3BP1-NTF2L:Caprin-1 GIM complex, in vitro LLPS assays with isolated domains, domain deletion/rescue experiments in cells with endogenous Caprin-1 knockout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro reconstitution of LLPS, and cellular rescue with domain mutants, multiple orthogonal methods\",\n      \"pmids\": [\"36279435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNG105/Caprin-1 deletion in mice impairs the asymmetric somato-dendritic localization of mRNAs encoding regulators of AMPAR surface expression, leading to attenuated homeostatic AMPAR scaling in dendrites, reduced synaptic strength and structural plasticity, and severe defects in long-term spatial and contextual memory formation.\",\n      \"method\": \"Conditional mouse knockout, genome-wide mRNA distribution profiling (in situ hybridization/sequencing), synaptic electrophysiology, behavioural memory tasks\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO with genome-wide mRNA localization profiling, electrophysiology, and behavioural readouts, multiple orthogonal methods\",\n      \"pmids\": [\"29157358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNG105 knockout in mice reduces dendritic localization of Na+/K+ ATPase subunit isoform mRNAs (α3, FXYD1, FXYD6, FXYD7), causing loss of NKA function specifically in dendrites without affecting somatic NKA, and impairing synapse formation and maintenance.\",\n      \"method\": \"Mouse knockout, in situ hybridization for mRNA localization, NKA activity assays in subcellular fractions, synapse quantification\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO with mRNA localization and functional enzymatic assays, replicated across multiple NKA subunit mRNAs\",\n      \"pmids\": [\"20861386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CAPRIN1 associates with thousands of RNA transcripts in embryonic stem cells and promotes their degradation through interaction with the ribonuclease XRN2; upon early ESC differentiation, XRN2 localizes to the nucleus and colocalizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner.\",\n      \"method\": \"CAPRIN1 knockout in mouse ESCs, RIP-seq, SLAM-seq, co-immunoprecipitation/interactome identification of XRN2, fluorescent protein library screen, immunofluorescence\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO combined with RIP-seq, SLAM-seq, and interactome identification, multiple orthogonal methods\",\n      \"pmids\": [\"36495875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon glutamine deprivation, lncRNA GIRGL drives formation of a complex between CAPRIN1 dimers and GLS1 mRNA, promoting liquid-liquid phase separation of CAPRIN1 and stress granule formation, which suppresses GLS1 mRNA translation.\",\n      \"method\": \"RNA pulldown, co-immunoprecipitation, in vitro phase separation assays, CAPRIN1 knockdown with GLS1 translation readout, lncRNA overexpression/knockdown\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown and LLPS reconstitution with functional translation readout, single lab\",\n      \"pmids\": [\"33762340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tylophorine directly binds Caprin-1 and enhances recruitment of G3BP1, c-Myc mRNA, and cyclin D2 mRNA into a ribonucleoprotein complex that is sequestered to polysomal fractions, repressing translation of associated mRNAs; Caprin-1-depleted cells are more resistant to tylophorine and show decreased RNP complex formation.\",\n      \"method\": \"Biotinylated tylophorine pulldown/affinity capture, co-immunoprecipitation, polysome fractionation, Caprin-1 siRNA knockdown, gene expression profiling\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity capture identifies direct binding, functional translation readout and loss-of-function confirmation, single lab\",\n      \"pmids\": [\"25669982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Caprin-1 directly interacts with Cyr61; ectopic Caprin-1 expression leads to formation of stress granules containing Caprin-1 and Cyr61, confers resistance to cisplatin-induced apoptosis, and constitutively activates Akt and ERK1/2 signaling.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, apoptosis assays, western blotting for Akt/ERK1/2 phosphorylation, in vivo xenograft model\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction plus functional signaling readout and in vivo model, single lab\",\n      \"pmids\": [\"23528710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX3X physically interacts and co-localizes with Caprin-1 and poly(A)-binding protein 1 (PABP1) at the leading edge of spreading/migrating fibroblasts; depletion of DDX3X decreases cell motility, linking the DDX3X-Caprin-1 interaction to cell migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, DDX3X depletion with motility assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and localization data with functional depletion phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"28733330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CAPRIN1 P512L mutation causes aberrant protein aggregation; overexpressed CAPRIN1-P512L forms insoluble ubiquitinated aggregates that sequester neurodegenerative disease-associated proteins (ATXN2, GEMIN5, SNRNP200, SNCA); P512L mutation in iPSC-derived cortical neurons reduces neuronal activity and alters stress granule dynamics; RNA strongly enhances CAPRIN1-P512L aggregation in vitro.\",\n      \"method\": \"Patient exome sequencing, isogenic iPSC neurons, overexpression/solubility assays, co-immunoprecipitation, nano-DSF, stress granule formation assays, MEA electrophysiology\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic human neuronal model with multiple orthogonal assays (biochemical aggregation, co-IP, electrophysiology, in vitro RNA-driven aggregation)\",\n      \"pmids\": [\"36136249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAPRIN1 haploinsufficiency in human iPSC-derived neurons causes reduced neuronal processes, disrupted neuronal organization, increased neurodegeneration, altered mRNA translation (consistent with translational inhibitor function), impaired calcium signaling, increased oxidative stress, and reduced neuronal network activity.\",\n      \"method\": \"CRISPR-Cas9 haploinsufficiency iPSC model, differentiation into neuronal progenitors and cortical neurons, micro-electrode arrays, calcium imaging, oxidative stress assays, translation assays\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic human neuronal model with multiple orthogonal functional readouts, CRISPR-controlled genetic manipulation\",\n      \"pmids\": [\"35979925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAPRIN1 interacts with ATG16L1 and mediates LC3 targeting of murine norovirus replication complexes; IFN-gamma-mediated control of MNV replication is dependent on CAPRIN1.\",\n      \"method\": \"Co-immunoprecipitation, CAPRIN1 knockdown/knockout, viral replication assays, IFN-gamma treatment\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction and CAPRIN1 loss-of-function with viral replication readout, single lab\",\n      \"pmids\": [\"37052473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR45 forms gel-like condensates via its WD5 domain that phase separate with Caprin-1; WDR45 competitively displaces G3BP1 from Caprin-1 to promote stress granule disassembly; BPAN-associated WDR45 mutations impair condensate formation and Caprin-1 interaction, leading to delayed SG disassembly.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phase separation assays, competitive binding assays, BPAN patient iPSC-derived neurons, SG dynamics assays, domain deletion mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cellular methods, disease mutation validation in patient-derived neurons\",\n      \"pmids\": [\"40473629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPRIN1 selectively binds STAT1 mRNA via the 5'UTR G-quadruplex (rG4) structure, stabilizes the rG4 conformation, halts ribosomal scanning, and suppresses STAT1 protein production; this suppresses interferon signaling; HBV polymerase functions as a transcription factor that upregulates CAPRIN1 expression during HBV infection.\",\n      \"method\": \"Ribonucleoprotein immunoprecipitation-MS, EMSA, luciferase reporter assays, ribosome profiling, circular dichroism, CAPRIN1 knockdown/re-expression in vitro and in vivo\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (RIP-MS, EMSA, ribosome profiling, CD) combined with loss-of-function and functional IFN readout\",\n      \"pmids\": [\"41951358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAPRIN1 interacts with NCOA4 mRNA via its RGG domain and recruits NCOA4 mRNA into stress granules, repressing NCOA4 translation and blunting sorafenib-induced ferroptosis in hepatocellular carcinoma; genetic disruption of CAPRIN1 restores NCOA4 expression and resensitizes resistant tumors to sorafenib.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, RGG domain mutagenesis, CAPRIN1 knockout, ferroptosis assays, in vivo xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP with domain mutagenesis and functional ferroptosis readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"41896589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPRIN1 regulates m6A modification of RIG-I mRNA through direct interaction with METTL3, influencing downstream interferon-associated gene networks and modulating M. tuberculosis infection; these processes predominantly occur within cellular stress granules.\",\n      \"method\": \"m6A RIP assay, co-immunoprecipitation (CAPRIN1-METTL3 interaction), CAPRIN1 knockdown, RIG-I m6A quantification, infection models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — m6A-RIP and Co-IP with functional infection readout, single lab, mechanistic link to METTL3 established biochemically\",\n      \"pmids\": [\"41198861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Caprin-1 binding to NMDA receptor 3B mRNA stabilizes it (demonstrated by circ288 binding to Caprin-1 and inhibiting its degradation, raising NMDAR3B mRNA levels); neuron-specific caprin-1 knockout mice lose the protective effect of circ288 overexpression, placing Caprin-1 upstream of NMDAR3B mRNA regulation.\",\n      \"method\": \"Neuron-specific Caprin-1 conditional knockout (CaMK2α-Cre:Caprin1f/f), AAV-mediated overexpression, mRNA stability assays, in vitro epilepsy model, RNA binding assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO epistasis places Caprin-1 upstream of NMDAR3B regulation, but mechanism is partially inferred from circRNA interaction context, single lab\",\n      \"pmids\": [\"39962265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Caprin-1 interacts with both ULK1 and STK38 in pancreatic cancer cells and manipulates ULK1 phosphorylation to activate autophagy, promoting pro-tumorigenic phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ULK1 phosphorylation assays, CAPRIN1 knockdown, autophagy flux assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP binding and phosphorylation assay from a single lab with limited mechanistic follow-up on the ULK1 activation mechanism\",\n      \"pmids\": [\"38082307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPRIN1 binds and stabilizes YY1 mRNA; YY1 then transcriptionally activates HSP90AA1; HSP90α binds and stabilizes IDH1 protein, protecting it from degradation; this cascade (CAPRIN1→YY1 mRNA stabilization→HSP90α→IDH1 stabilization) suppresses ferroptosis and promotes cisplatin resistance in cervical cancer.\",\n      \"method\": \"RNA immunoprecipitation, RNA pulldown, actinomycin D mRNA stability assay, dual-luciferase/ChIP assay for YY1-HSP90AA1, co-IP for HSP90α-IDH1, CAPRIN1 knockdown + IDH1 rescue, xenograft model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pulldown for Caprin-1 mRNA binding, multiple epistasis steps validated biochemically, rescue experiments confirm pathway, single lab\",\n      \"pmids\": [\"42114793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Caprin-1 FMRP-interacting helix is part of an integral α-helix in the HR1 homodimeric structure (Caprin-2 comparison); HR1 dimerization is an evolutionarily conserved feature of the caprin family, and different molecular surface properties between Caprin-1 and Caprin-2 dimers likely dictate specificity for distinct protein partners.\",\n      \"method\": \"X-ray crystallography of Caprin-2 HR1 fragment, structural comparison with Caprin-1 structure\",\n      \"journal\": \"Journal of biomolecular structure & dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of Caprin-2 with structural inference for Caprin-1, single lab, functional validation limited\",\n      \"pmids\": [\"30304999\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAPRIN1 is an RNA-binding protein that functions as a core scaffold of stress granules and neuronal RNA granules: it binds G3BP1 via a conserved SLiM (promoting stress granule condensation through its C-terminal IDR-driven phase separation), directly interacts with FMRP and PKR to form an RNP complex that regulates mRNA translation and innate immune PKR activation, selectively binds c-Myc and cyclin D2 mRNAs through its RGG motifs to control their translation, mediates dendritic mRNA localization essential for synaptic plasticity and long-term memory, undergoes phosphorylation- and O-GlcNAcylation-regulated liquid-liquid phase separation driven by arginine-aromatic interactions in its C-terminal IDR, is subject to SPOP-mediated ubiquitin-dependent degradation, promotes RNA degradation via XRN2 during stem cell differentiation, and suppresses STAT1 translation by stabilizing an rG4 structure in the STAT1 5'UTR to dampen interferon signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAPRIN1 is an RNA-binding protein that serves as a core scaffold of cytoplasmic RNA granules, coupling mRNA fate control to stress and developmental signaling [#0, #2]. It engages G3BP1 through a conserved short linear motif (FxQDSxxD) that docks onto a distinct site on the G3BP1 NTF2-like domain involving His-31/His-62, binding mutually exclusively with USP10 [#0, #2, #11]; while this interaction modulates G3BP1, CAPRIN1 drives stress granule condensation chiefly through liquid-liquid phase separation of its C-terminal intrinsically disordered region, governed by arginine-aromatic side-chain interactions and tuned by tyrosine phosphorylation, O-GlcNAcylation, and ATP [#5, #10, #12]. CAPRIN1 homodimerizes via an all-\\u03b1-helical HR1 domain that also forms the FMRP-interacting interface, allowing it to co-phase-separate with FMRP and modulate deadenylation and translation [#5, #9]. Through its C-terminal RGG motifs CAPRIN1 selectively binds target transcripts including c-Myc and cyclin D2 mRNAs to control their translation, consistent with its requirement for G1-S cell cycle progression [#0, #1]. CAPRIN1 also forms an RNP complex with PKR that supports stress-granule-dependent PKR activation and antiviral defense, and is required with G3BP for efficient translation of interferon-stimulated mRNAs, making it a frequent target of viral antagonists [#3, #6, #7]. In neurons, CAPRIN1 (RNG105) directs asymmetric dendritic localization of mRNAs encoding AMPAR regulators and Na+/K+-ATPase subunits, supporting synapse formation, homeostatic plasticity, and long-term memory [#13, #14]. CAPRIN1 protein abundance is set by SPOP-mediated ubiquitin-dependent degradation, and CAPRIN1 mutations and haploinsufficiency cause aberrant aggregation, disrupted stress granule dynamics, and neurodegenerative phenotypes in patient-derived neurons [#4, #20, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that CAPRIN1 has an essential cellular function, before any molecular activity was known, motivated mechanistic dissection of how it controls proliferation.\",\n      \"evidence\": \"Conditional homologous-recombination knockout in DT40 B cells with rescue and cell-cycle flow cytometry\",\n      \"pmids\": [\"16177067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular activity underlying the G1 prolongation\", \"No RNA targets linked to the proliferation phenotype at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined CAPRIN1 as a sequence-specific RNA-binding protein and G3BP1 partner, establishing the molecular basis for its role in stress granules and translational control of growth genes.\",\n      \"evidence\": \"Co-IP, GST pulldown, RGG-motif mutagenesis, eIF2\\u03b1 phosphorylation and stress granule assays with confocal imaging\",\n      \"pmids\": [\"17210633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect mode of c-Myc/cyclin D2 translational control not resolved\", \"Structural basis of the G3BP1 motif interaction not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CAPRIN1 to neuronal mRNA transport and to viral antagonism, showing it operates in both FMRP-containing neuronal RNP granules and as a host antiviral target.\",\n      \"evidence\": \"Reciprocal Co-IP and polysome fractionation for FMRP (neurons); affinity-MS and mutagenesis for JEV core protein binding with in vivo virulence\",\n      \"pmids\": [\"22737234\", \"23097442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FMRP/CAPRIN1 shared-target work limited to two mRNAs and a single lab\", \"Functional consequence of FMRP co-association on translation not measured directly here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CAPRIN1 organizes innate immune signaling complexes, demonstrating it directly binds PKR and is required for ISG mRNA translation, positioning stress granules as antiviral signaling platforms.\",\n      \"evidence\": \"GST pulldown, Co-IP, PKR activation assays, polysome translation assays, siRNA, viral infection models\",\n      \"pmids\": [\"25784705\", \"24992036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CAPRIN1 mechanistically promotes ISG-mRNA translation not resolved\", \"Stoichiometry of the G3BP1-CAPRIN1-PKR complex undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the architecture and competitive logic of CAPRIN1 within stress granules, showing CAPRIN1 and USP10 bind G3BP1 mutually exclusively to oppositely tune condensation, and that CAPRIN1 self-associates through a novel helical dimerization fold.\",\n      \"evidence\": \"G3BP1/2 double-KO rescue with point mutants and Co-IP; X-ray crystallography of the CAPRIN1 dimerization domain\",\n      \"pmids\": [\"27022092\", \"27303792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CAPRIN1/USP10 binding shown not strictly required for SG nucleation, leaving its precise contribution unclear\", \"Functional role of the negatively charged dimer surface not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated the physiological output of CAPRIN1-dependent mRNA localization, linking dendritic transport of plasticity-related mRNAs to synaptic strength, homeostatic scaling, and memory.\",\n      \"evidence\": \"Conditional mouse KO with genome-wide mRNA distribution profiling, electrophysiology, and behavioural memory tasks; earlier KO defining NKA-subunit mRNA dependence\",\n      \"pmids\": [\"29157358\", \"20861386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA-binding selectivity within dendritic transport granules not fully mapped\", \"Whether phase separation drives dendritic localization in vivo untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the post-translational control of CAPRIN1 abundance and reconstituted its phase behavior with FMRP, establishing how condensate composition and phosphorylation tune translation and deadenylation.\",\n      \"evidence\": \"Y2H/Co-IP/ubiquitination assays for SPOP; NMR of FMRP-CAPRIN1 condensates with in vitro translation/deadenylation and phosphomimetics\",\n      \"pmids\": [\"31771591\", \"31439799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of SPOP-CAPRIN1 degradation outside cancer contexts unclear\", \"Kinases setting CAPRIN1 tyrosine phosphorylation in cells not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established at atomic and biophysical resolution how CAPRIN1 drives stress granule formation, showing the C-terminal IDR (not the G3BP1 motif) provides the phase-separating activity and defining the G3BP1-binding site and its pH dependence.\",\n      \"evidence\": \"Crystal structures of G3BP1-NTF2L:CAPRIN1 GIM, in vitro LLPS reconstitution with isolated domains, nanoDSF, and live-cell pH measurement\",\n      \"pmids\": [\"36279435\", \"37161291\", \"34074792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of GIM binding vs IDR LLPS to granules in vivo not fully separated\", \"Physiological triggers of the pH-dependent partner switch unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CAPRIN1 dysfunction to human neurodegeneration, showing a point mutation and haploinsufficiency cause aberrant aggregation, altered stress granule dynamics, and impaired neuronal activity.\",\n      \"evidence\": \"Patient exome sequencing with isogenic iPSC-derived neurons, solubility/aggregation assays, nanoDSF, MEA electrophysiology, CRISPR haploinsufficiency model\",\n      \"pmids\": [\"36136249\", \"35979925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting aggregation to specific neuronal deficits incompletely defined\", \"Whether loss-of-function and gain-of-toxicity contribute differently not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CAPRIN1 as a regulated node in stress granule disassembly and degradative pathways, partnering with WDR45 and XRN2.\",\n      \"evidence\": \"Co-IP, in vitro phase separation/competition assays, BPAN patient iPSC neurons (WDR45); KO with RIP-seq/SLAM-seq and interactome (XRN2)\",\n      \"pmids\": [\"40473629\", \"36495875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WDR45 displacement is triggered physiologically not defined\", \"Selectivity rules for CAPRIN1/XRN2-targeted transcripts in ESCs unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CAPRIN1 to structured-RNA recognition and disease-context translational control, showing it stabilizes a STAT1 5'UTR rG4 to dampen interferon signaling and acts in multiple cancer and infection programs.\",\n      \"evidence\": \"RIP-MS, EMSA, ribosome profiling, CD for STAT1 rG4; RIP/RGG mutagenesis and functional readouts for NCOA4, METTL3/RIG-I, NMDAR3B, and YY1 axes\",\n      \"pmids\": [\"41951358\", \"41896589\", \"41198861\", \"39962265\", \"42114793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most downstream axes rest on single-lab studies\", \"General rules distinguishing CAPRIN1-mediated stabilization from degradation/repression of bound transcripts not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAPRIN1's modular activities — RGG-mediated transcript selection, IDR phase separation, dimerization, and post-translational modification — are integrated to specify which mRNAs are localized, stabilized, or repressed in a given context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking condensate state to transcript-specific fate\", \"Context-dependent switch between translational repression and mRNA stabilization undefined\", \"Physiological signals controlling CAPRIN1 PTMs in vivo unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 15, 24, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 11, 12]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 5, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 15, 24]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6, 24, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 14, 21, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"complexes\": [\"stress granule\", \"G3BP1-CAPRIN1-PKR complex\", \"FMRP-CAPRIN1 ribonucleoprotein granule\"],\n    \"partners\": [\"G3BP1\", \"FMRP\", \"PKR\", \"USP10\", \"XRN2\", \"WDR45\", \"SPOP\", \"DDX3X\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}