{"gene":"CAPRIN1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CAPRIN1 contains a highly conserved motif (F(M/I/L)Q(D/E)Sx(I/L)D) that directly binds the NTF2-like domain of G3BP1; the C-terminal RGG motifs of CAPRIN1 selectively bind c-Myc and cyclin D2 mRNAs; overexpression of CAPRIN1 induces eIF2α phosphorylation (requiring its RNA-binding ability) and stress granule formation; CAPRIN1 co-localizes with G3BP1 in cytoplasmic RNA granules associated with microtubules at the leading/trailing edges of migrating cells.","method":"Mutagenesis of GIM motif and RGG motifs, co-immunoprecipitation, RNA-binding assays, immunofluorescence/live imaging, eIF2α phosphorylation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (mutagenesis, co-IP, RNA pulldown, functional assays) in a single foundational study","pmids":["17210633"],"is_preprint":false},{"year":2005,"finding":"CAPRIN1 is required for normal G1-S cell cycle progression; homozygous disruption of caprin-1 in DT40 cells markedly reduces proliferation rate due to prolongation of G1 phase, demonstrating an essential role in cellular proliferation.","method":"Homologous recombination knockout in DT40 cells, conditional expression rescue, cell cycle analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cell cycle phenotype and conditional rescue confirming specificity","pmids":["16177067"],"is_preprint":false},{"year":2016,"finding":"CAPRIN1 and USP10 bind mutually exclusively to the NTF2-like domain of G3BP1; Caprin1 binding promotes SG formation while USP10 binding inhibits it; G3BP1-F33W mutant (unable to bind Caprin1 or USP10) still rescues SG formation, indicating Caprin1/USP10 modulate rather than absolutely require G3BP1 for SG condensation; G3BP interacts with 40S ribosomal subunits through its RGG motif.","method":"G3BP1/2 double knockout cells, rescue with G3BP1 phosphomimetic/binding mutants, co-immunoprecipitation, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic and biochemical dissection in DKO cells with multiple mutants, replicated findings","pmids":["27022092"],"is_preprint":false},{"year":2015,"finding":"CAPRIN1 directly interacts with PKR (double-stranded RNA-dependent protein kinase) and forms a G3BP1-Caprin1-PKR complex; Caprin1 regulates efficient PKR activation at stress granules and is required for release of active PKR into the cytoplasm for substrate recognition; this complex is important for antiviral activity during mengovirus infection.","method":"Direct binding assays, co-immunoprecipitation, mengovirus infection model, PKR activity assays, SG localization studies","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — direct interaction established with multiple biochemical methods plus functional viral infection readout","pmids":["25784705"],"is_preprint":false},{"year":2019,"finding":"Phase separation of CAPRIN1 and FMRP C-terminal intrinsically disordered regions is driven by arginine-rich and aromatic-rich region interactions; different phosphorylation patterns (FMRP serine/threonine, CAPRIN1 tyrosine) control phase separation propensity and modulate deadenylation and translation rates within condensates in vitro.","method":"NMR spectroscopy of condensed phases, phosphomimetic mutagenesis, in vitro deadenylation and translation assays, liquid-liquid phase separation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — NMR structural data combined with mutagenesis and in vitro enzymatic reconstitution","pmids":["31439799"],"is_preprint":false},{"year":2014,"finding":"CAPRIN1 (along with G3BP1 and G3BP2) is required for translation of interferon-stimulated gene (ISG) mRNAs including PKR and IFITM2; dengue virus sfRNA binds to CAPRIN1 (and G3BP1/2) to sequester them, inhibiting ISG mRNA translation as an immune evasion mechanism.","method":"siRNA knockdown, polysome profiling, RNA immunoprecipitation, viral infection assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined translational phenotype plus viral RNA binding assays","pmids":["24992036"],"is_preprint":false},{"year":2012,"finding":"Japanese encephalitis virus (JEV) core protein interacts with CAPRIN1 (identified by affinity capture mass spectrometry); residues Lys97 and Arg98 in the JEV core protein α-helix are critical for Caprin-1 binding; this interaction inhibits stress granule formation and facilitates viral propagation and virulence in mice.","method":"Affinity capture mass spectrometry, alanine scanning mutagenesis, mutant virus infection assays, in vivo mouse virulence model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — MS identification plus mutagenesis with in vitro and in vivo functional validation","pmids":["23097442"],"is_preprint":false},{"year":2012,"finding":"CAPRIN1 interacts with FMRP in neuronal ribonucleoprotein complexes; they co-associate with mRNAs including CaMKIIα and Map1b; the complex is present in polysomes and neuronal trafficking granules, suggesting CAPRIN1 modulates FMRP-dependent translation regulation.","method":"Immunoprecipitation with monoclonal and chicken antibodies, in vitro binding, polysome fractionation, neuronal granule co-localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and in vitro binding with fractionation, single laboratory","pmids":["22737234"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of a CAPRIN1 fragment (residues 132–251) reveals a novel all-α-helical fold that mediates homodimerization; dimerization creates a large negatively charged concave surface that functions as a protein-binding groove for partners including FMRP; the FMRP-interacting motif forms an integral helix that does not disrupt dimerization; structural basis for an RNP complex of Caprin1-FMRP-G3BP1 is proposed.","method":"X-ray crystallography, structural analysis, biochemical binding data integration","journal":"Acta crystallographica Section D","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis-guided interpretation and integration with existing biochemical data","pmids":["27303792"],"is_preprint":false},{"year":2021,"finding":"NMR studies of condensed CAPRIN1 C-terminal IDR (residues 607–709) identify specific side-chain and backbone interactions driving phase separation; ATP interactions with CAPRIN1 can enhance or reduce phase separation; O-GlcNAcylation of specific residues reduces phase separation propensity; arginine-containing N-terminal region is critical for phase separation relative to other Arg-rich stretches.","method":"NMR spectroscopy of condensed phase, mutagenesis, ATP titration, O-GlcNAcylation studies","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution NMR with mutagenesis validation, multiple orthogonal approaches","pmids":["34074792"],"is_preprint":false},{"year":2010,"finding":"RNG105 (Caprin1/mouse ortholog) knock-out in mice reduces dendritic localization of mRNAs encoding Na+/K+ ATPase subunit isoforms (α3, FXYD1, FXYD6, FXYD7), leading to loss of NKA function in dendrites without affecting somatic NKA; this impairs synapse formation and neuronal network maintenance.","method":"Caprin1 knockout mice, subcellular mRNA fractionation, electrophysiology, synapse morphology analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined mRNA localization and functional synaptic phenotype","pmids":["20861386"],"is_preprint":false},{"year":2017,"finding":"RNG105/Caprin1 deletion in mice causes severe deficits in long-term memory formation in spatial and contextual tasks; genome-wide mRNA profiling revealed RNG105 deficiency impairs asymmetric somato-dendritic localization of mRNAs including those encoding regulators of AMPAR surface expression; this is associated with attenuated homeostatic AMPAR scaling and reduced synaptic strength.","method":"Caprin1 KO mice, behavioral testing, genome-wide mRNA distribution profiling (hippocampus), electrophysiology, AMPAR surface expression assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined behavioral, molecular, and electrophysiological phenotypes, multiple orthogonal methods","pmids":["29157358"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of G3BP1-NTF2 domain in complex with Caprin-1-derived short linear motif (SLiM) shows Caprin-1 interacts with His-31 and His-62 within a third NTF2-binding site distinct from USP10's sites; G3BP1-NTF2 thermal stability is reduced at acidic pH and is counterbalanced better by USP10 than Caprin-1; acidification of condensates by ~0.5 pH units detected by ratiometric fluorescence; Caprin-1 N-terminal GIM suppresses G3BP1 LLPS while Caprin-1 C-terminal domain promotes LLPS, creating 'yin and yang' regulation of SG formation.","method":"X-ray crystallography, nano-differential scanning fluorimetry, biochemical binding assays, live cell ratiometric fluorescence (pHluorin2-G3BP1), in vitro LLPS assays","journal":"Open biology / Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1–2 — crystal structures from two independent studies combined with LLPS functional dissection and live cell measurements","pmids":["37161291","36279435"],"is_preprint":false},{"year":2019,"finding":"Wild-type SPOP (E3 ubiquitin ligase adaptor) recognizes CAPRIN1 and triggers its ubiquitin-dependent degradation; prostate cancer-associated SPOP mutants fail to degrade CAPRIN1, leading to elevated CAPRIN1 and aberrant stress granule assembly; this confers resistance to docetaxel and other SG inducers in prostate cancer cells.","method":"Yeast two-hybrid identification, co-immunoprecipitation, ubiquitination assays, SPOP mutant expression, xenograft models, patient specimen analysis","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — SPOP-CAPRIN1 interaction established biochemically with functional ubiquitination and in vivo xenograft validation","pmids":["31771591"],"is_preprint":false},{"year":2022,"finding":"CAPRIN1 knockout in mouse ESCs significantly alters differentiation and gene expression programs; CAPRIN1 associates with thousands of RNA transcripts (by RIP-seq) and promotes their degradation via interaction with the ribonuclease XRN2; upon early ESC differentiation, XRN2 localizes to the nucleus and co-localizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner.","method":"CAPRIN1 KO in mouse ESCs, RIP-seq, SLAM-seq (metabolic RNA labeling), immunoprecipitation/mass spectrometry interactome, immunofluorescence co-localization","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — KO phenotype combined with transcriptome-wide RIP-seq and interactome identifying XRN2 as functional partner","pmids":["36495875"],"is_preprint":false},{"year":2013,"finding":"Caprin-1 interacts with Cyr61 (extracellular matrix protein); stable ectopic expression of Caprin-1 leads to stress granules containing both Caprin-1 and Cyr61, constitutive phosphorylation of Akt and ERK1/2, resistance to cisplatin-induced apoptosis, and dramatically enhanced tumor growth and lung metastasis in osteosarcoma xenograft models.","method":"Co-immunoprecipitation, confocal microscopy, ectopic expression, xenograft mouse models, phospho-western blotting","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus functional in vivo xenograft data; pathway placement (Akt/ERK) by western blot only","pmids":["23528710"],"is_preprint":false},{"year":2021,"finding":"The Caprin-1 protein interactome (by endogenous IP-MS) in stressed and unstressed conditions identifies 1543 interacting proteins; stress-induced interactors include ribosome, spliceosome, and RNA transport pathway proteins; novel SG components ANKHD1, TALIN-1, GEMIN5, and SNRNP200 were validated as Caprin-1 stress-induced interactors localizing to arsenite-induced stress granules.","method":"Immunoprecipitation coupled with mass spectrometry, validation by co-IP and immunofluorescence in multiple cell lines","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2–3 — large-scale MS interactome with validation of selected hits; single laboratory","pmids":["33939924"],"is_preprint":false},{"year":2021,"finding":"CAPRIN1 promotes liquid-liquid phase separation when bound by the lncRNA GIRGL; GIRGL drives formation of a complex between CAPRIN1 dimers and GLS1 mRNA, inducing stress granule formation and translational suppression of GLS1 (glutaminase-1) mRNA under glutamine deprivation.","method":"RIP assay, LLPS assays, RNA-FISH, CAPRIN1 knockdown/overexpression, translational reporter assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple methods in a single laboratory establishing CAPRIN1-lncRNA-mRNA complex driving phase separation","pmids":["33762340"],"is_preprint":false},{"year":2022,"finding":"circVAMP3 drives phase separation of CAPRIN1 and promotes stress granule formation; this suppresses c-Myc mRNA translation, reducing c-Myc protein levels and inhibiting HCC cell proliferation and metastasis in vitro and in vivo.","method":"circRNA overexpression, LLPS assays, stress granule imaging, polysome profiling, translation reporter assays, xenograft models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — circRNA-CAPRIN1 phase separation with defined translational consequence, single laboratory","pmids":["35072355"],"is_preprint":false},{"year":2017,"finding":"DDX3X helicase physically interacts and co-localizes with CAPRIN1 and poly(A)-binding protein 1 (PABP1) at the leading edge of spreading fibroblasts; depletion of DDX3X leads to decreased cell motility, providing a functional link between DDX3X, Caprin-1, and initiation factors at the leading edge to promote cell migration.","method":"Co-immunoprecipitation, immunofluorescence co-localization, DDX3X depletion with cell motility/spreading assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and co-localization with functional KD phenotype; single laboratory, modest follow-up on CAPRIN1's specific contribution","pmids":["28733330"],"is_preprint":false},{"year":2022,"finding":"NMR measurement of per-residue near-surface electrostatic potentials of the positively charged C-terminal IDR of CAPRIN1 along ATP-induced phase separation reveals that electrostatic shielding by ATP decreases surface potentials, promotes interchain interactions between aromatic-rich and arginine-rich regions, and drives phase separation; at high ATP, CAPRIN1 becomes negatively charged and re-enters the mixed phase.","method":"Solution NMR (paramagnetic relaxation enhancement, chemical shift perturbation), ATP titration, phase separation assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — atomic resolution NMR along phase separation trajectory with mechanistic model validated by multiple measurements","pmids":["36040869"],"is_preprint":false},{"year":2023,"finding":"CAPRIN1 interacts with ATG16L1 and WIPI2B to mediate LC3 targeting of murine norovirus (MNV) replication complexes; IFN-γ-mediated control of MNV replication is dependent on CAPRIN1.","method":"Co-immunoprecipitation, CAPRIN1 depletion in viral replication assays, IFN-γ treatment experiments","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2–3 — interaction identified with co-IP and confirmed by loss-of-function with viral replication readout; single laboratory","pmids":["37052473"],"is_preprint":false},{"year":2024,"finding":"CAPRIN1 condensates shift the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble; key contacts are between CAPRIN1 arginine-rich/aromatic-rich regions and the H80-H120 region of unfolded SOD1; unfolding of immature SOD1 in the CAPRIN1 condensed phase is coupled to aggregation.","method":"Solution NMR spectroscopy (mixed phase and demixed CAPRIN1 condensates), intermolecular NOE, PRE experiments","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution NMR in condensed phase with mechanistic mapping of interaction sites","pmids":["39172789"],"is_preprint":false},{"year":2022,"finding":"CAPRIN1-P512L de novo missense variant causes aberrant protein aggregation; overexpressed CAPRIN1-P512L forms insoluble ubiquitinated aggregates sequestering ATXN2, GEMIN5, SNRNP200, and SNCA; iPSC-derived cortical neurons with this mutation show reduced neuronal activity, altered stress granule dynamics, and enhanced RNA-promoted aggregation in vitro.","method":"Protein solubility assays, co-aggregation by co-IP/western blot, iPSC-derived neuron electrophysiology, nano-DSF, stress granule dynamics imaging","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function mutation with multiple cellular and biochemical readouts; single laboratory","pmids":["36136249"],"is_preprint":false},{"year":2025,"finding":"WDR45 forms gel-like condensates via its WD5 domain and 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, phase separation assays, competitive binding assays, iPSC-derived midbrain neurons from BPAN patient, stress granule dynamics imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection of WDR45-Caprin1 interaction with patient-derived neuron validation; single laboratory","pmids":["40473629"],"is_preprint":false},{"year":2025,"finding":"CAPRIN1 interacts with METTL3 and regulates m6A modification of RIG-I mRNA; this interaction and m6A regulatory activity occurs within cellular stress granules; CAPRIN1 modulates interferon-associated gene networks and M. tuberculosis infection responses.","method":"Co-immunoprecipitation with METTL3, m6A-RIP, stress granule localization studies, CAPRIN1 knockdown in infection models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — novel interaction with defined m6A writer established by co-IP and RIP; single laboratory, emerging mechanism","pmids":["41198861"],"is_preprint":false},{"year":2026,"finding":"CAPRIN1 stabilizes the G-quadruplex (rG4) structure in the 5'UTR of STAT1 mRNA, halting ribosomal scanning and suppressing STAT1 protein translation; CAPRIN1 interacts with STAT1 rG4 (demonstrated by EMSA, luciferase reporter, and ribosome profiling); HBV polymerase functions as a transcription factor driving CAPRIN1 expression, causing IFN resistance.","method":"RIP-mass spectrometry, EMSA, luciferase reporter assays, ribosome profiling, circular dichroism, CAPRIN1 knockdown in vitro and in vivo","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EMSA, ribosome profiling, RIP-MS) establishing rG4 binding and translational repression; single laboratory","pmids":["41951358"],"is_preprint":false},{"year":2023,"finding":"circIPO7 directly binds Caprin-1 at sites overlapping with the G3BP1-binding region, blocking the Caprin-1–G3BP1 interaction and dissociating Caprin-1 and its target mRNAs (EGFR and mTOR mRNAs) from ribosomes, resulting in their translational inhibition and PI3K/AKT/mTOR pathway inactivation in gastric cancer.","method":"RNA pull-down, RIP assay, polysome fractionation, co-immunoprecipitation competition assays, cell proliferation assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNA-protein interaction mapped by pull-down/RIP with defined translational and signaling consequences; single laboratory","pmids":["36732659"],"is_preprint":false},{"year":2023,"finding":"CAPRIN1 interacts with ULK1 and STK38, manipulating ULK1 phosphorylation to activate autophagy and promote tumor growth in pancreatic cancer.","method":"Co-immunoprecipitation, phosphorylation assays, loss-of-function studies with autophagy readout, xenograft models","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP with phosphorylation assay; pathway placement indirect; single laboratory","pmids":["38082307"],"is_preprint":false},{"year":2026,"finding":"CAPRIN1 mediates sorafenib resistance in hepatocellular carcinoma by interacting with NCOA4 mRNA via its RGG domain and recruiting NCOA4 mRNA into stress granules, repressing NCOA4 translation and blunting sorafenib-induced ferroptosis.","method":"Co-immunoprecipitation, RIP assay, stress granule imaging, translation reporter, CAPRIN1 KO rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — RGG-domain-specific RNA interaction with translational and functional consequences; single laboratory","pmids":["41896589"],"is_preprint":false},{"year":2025,"finding":"NAT10 promotes ac4C (N4-acetylcytidine) modification of CAPRIN1 mRNA, stabilizing it and increasing CAPRIN1 protein expression; NAT10 knockdown reduces ac4C levels on CAPRIN1 mRNA and decreases its stability.","method":"ac4C-RIP, actinomycin D mRNA stability assay, NAT10 knockdown, CAPRIN1 overexpression rescue","journal":"BMC women's health","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNA modification writer identified with stability assay; established ac4C-RIP; single laboratory","pmids":["39923057"],"is_preprint":false},{"year":2025,"finding":"CAPRIN1 NMR studies in CAPRIN1 condensates reveal that FUS RRM (a client) partitions 30-fold into CAPRIN1 condensates via interactions between FUS RRM and aromatic-rich and arginine-rich regions of CAPRIN1; tyrosine phosphorylation of CAPRIN1 disrupts these interactions and reduces client partitioning by over 100-fold.","method":"Solution NMR (HSQC, intermolecular NOE, PRE), chemical shift perturbation in mixed/demixed phases","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution NMR mapping of client-scaffold interactions within condensates, with PTM effect validated","pmids":["40857360"],"is_preprint":false}],"current_model":"CAPRIN1 is a cytoplasmic RNA-binding phosphoprotein that forms an RNP complex with G3BP1 and FMRP; it selectively binds specific mRNAs (c-Myc, cyclin D2, STAT1) via its C-terminal RGG motifs to regulate their translation, recruits PKR for antiviral innate immune activation, drives liquid-liquid phase separation via arginine/aromatic-rich IDR interactions that are tuned by phosphorylation and ATP, undergoes ubiquitin-dependent degradation by SPOP (opposing its SG-promoting activity), mediates dendritic mRNA localization essential for synaptic plasticity and long-term memory, and promotes RNA degradation during ESC differentiation through interaction with XRN2."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that CAPRIN1 is required for cell proliferation answered whether the gene has a cell-autonomous growth function, revealing it as essential for G1-to-S progression.","evidence":"Homologous recombination knockout in DT40 cells with conditional rescue and cell cycle analysis","pmids":["16177067"],"confidence":"High","gaps":["Mechanism of G1-S promotion unknown — target mRNAs not yet identified","No mammalian in vivo proliferation data at this point"]},{"year":2007,"claim":"Identification of the G3BP1-binding GIM motif and the RNA-binding RGG motifs defined CAPRIN1 as a modular RNA-granule scaffold that selectively binds c-Myc and cyclin D2 mRNAs and induces stress granule formation via eIF2α phosphorylation.","evidence":"Mutagenesis of GIM and RGG motifs, co-IP, RNA-binding assays, eIF2α phosphorylation, immunofluorescence","pmids":["17210633"],"confidence":"High","gaps":["Structural basis of GIM–NTF2 interaction unresolved","Mechanism linking CAPRIN1 overexpression to eIF2α phosphorylation not delineated"]},{"year":2010,"claim":"Knockout mice revealed that CAPRIN1 controls dendritic mRNA localization of Na⁺/K⁺-ATPase subunit transcripts, establishing its role in neuronal compartment-specific translation and synapse maintenance.","evidence":"Caprin1 KO mice with subcellular mRNA fractionation, electrophysiology, synapse morphology","pmids":["20861386"],"confidence":"High","gaps":["Whether CAPRIN1 directly transports these mRNAs or acts indirectly through granule partners not resolved","Behavioral consequences not yet tested"]},{"year":2012,"claim":"Discovery that CAPRIN1 interacts with FMRP in neuronal RNP complexes on polysomes, and that viral core proteins (JEV) hijack CAPRIN1 to suppress stress granules, established CAPRIN1 as both a neuronal translational regulator and a viral target.","evidence":"Co-IP/in vitro binding with polysome fractionation (FMRP); affinity-capture MS with mutagenesis and in vivo virulence (JEV)","pmids":["22737234","23097442"],"confidence":"High","gaps":["Structural basis of CAPRIN1–FMRP interaction unknown","Whether FMRP and G3BP1 bind CAPRIN1 simultaneously or competitively not tested"]},{"year":2014,"claim":"Demonstrating that CAPRIN1/G3BP1/G3BP2 are required for ISG mRNA translation, and that dengue sfRNA sequesters them, revealed CAPRIN1 as a positive translational regulator of innate immune transcripts and a target of viral immune evasion.","evidence":"siRNA knockdown, polysome profiling, RNA immunoprecipitation, dengue infection assays","pmids":["24992036"],"confidence":"High","gaps":["Whether CAPRIN1 directly loads ISG mRNAs onto ribosomes or acts via G3BP unclear","Breadth of ISG mRNA targets not comprehensively mapped"]},{"year":2015,"claim":"Identification of a G3BP1–CAPRIN1–PKR complex that activates PKR at stress granules and releases it for antiviral signaling established CAPRIN1 as a platform for innate immune kinase activation.","evidence":"Direct binding assays, co-IP, PKR activity assays, mengovirus infection model","pmids":["25784705"],"confidence":"High","gaps":["Whether CAPRIN1 allosterically activates PKR or merely concentrates it in granules not distinguished","Generalizability beyond mengovirus not tested"]},{"year":2016,"claim":"Structural and genetic dissection showed that CAPRIN1 and USP10 compete for the same G3BP1-NTF2 surface with opposing effects on stress granule condensation, and that CAPRIN1 homodimerizes via a novel α-helical fold creating a binding groove for FMRP.","evidence":"G3BP1/2 DKO rescue with mutants; X-ray crystallography of CAPRIN1 fragment (residues 132–251)","pmids":["27022092","27303792"],"confidence":"High","gaps":["Full-length structure of CAPRIN1–G3BP1–FMRP ternary complex not determined","How CAPRIN1 dimerization affects RNA binding not tested"]},{"year":2017,"claim":"Caprin1 KO mice showed severe long-term memory deficits with impaired dendritic mRNA asymmetry and attenuated AMPA receptor homeostatic scaling, establishing CAPRIN1 as essential for synaptic plasticity and cognitive function.","evidence":"KO mice, behavioral testing, genome-wide mRNA profiling, electrophysiology, AMPAR surface expression","pmids":["29157358"],"confidence":"High","gaps":["Whether the memory deficit is cell-autonomous to excitatory neurons not resolved","Contribution of individual CAPRIN1-dependent mRNAs to the phenotype not dissected"]},{"year":2019,"claim":"NMR and phosphomimetic studies revealed that CAPRIN1 C-terminal IDR phase separation is driven by arginine–aromatic interactions and tuned by differential phosphorylation, providing the biophysical basis for stress granule condensation; separately, SPOP was identified as the E3 ligase adaptor mediating CAPRIN1 ubiquitin-dependent degradation, with cancer-associated SPOP mutants stabilizing CAPRIN1 and promoting aberrant SG assembly.","evidence":"NMR of condensed phases, phosphomimetic mutagenesis, in vitro deadenylation/translation (phase separation); yeast two-hybrid, ubiquitination assays, xenograft models (SPOP)","pmids":["31439799","31771591"],"confidence":"High","gaps":["Which kinases phosphorylate CAPRIN1 tyrosines in vivo not identified","Whether SPOP-mediated degradation occurs at stress granules or in the soluble phase unknown"]},{"year":2021,"claim":"Atomic-resolution NMR mapped specific side-chain contacts driving CAPRIN1 phase separation and showed that ATP and O-GlcNAcylation bidirectionally modulate condensation, while noncoding RNAs (lncRNA GIRGL) were found to promote CAPRIN1 LLPS and translational repression of specific mRNAs.","evidence":"NMR with mutagenesis and ATP/O-GlcNAc titrations; RIP, LLPS assays, translational reporters for GIRGL","pmids":["34074792","33762340"],"confidence":"High","gaps":["In vivo O-GlcNAcylation stoichiometry on CAPRIN1 not determined","How lncRNA binding remodels CAPRIN1 IDR conformation not structurally resolved"]},{"year":2022,"claim":"Crystal structures of G3BP1-NTF2 with Caprin-1 SLiM revealed a distinct binding site (His-31/His-62), and functional studies demonstrated that CAPRIN1's N-terminal GIM suppresses while its C-terminal domain promotes LLPS, establishing 'yin-and-yang' regulation; separately, CAPRIN1 was shown to promote RNA degradation via XRN2 in ESC differentiation, and a disease-linked P512L variant caused aberrant aggregation with sequestration of neurodegeneration-associated proteins.","evidence":"X-ray crystallography, nano-DSF, LLPS assays, ratiometric fluorescence (G3BP1-NTF2); CAPRIN1 KO ESCs, RIP-seq, SLAM-seq (XRN2); iPSC-derived neurons, solubility assays (P512L)","pmids":["36279435","37161291","36495875","36136249"],"confidence":"High","gaps":["Whether pH-dependent SG regulation via His residues operates in physiological stress not tested in vivo","XRN2 recruitment mechanism to CAPRIN1 granules not structurally defined","P512L disease causality in humans requires genetic replication"]},{"year":2023,"claim":"CAPRIN1 was linked to autophagy-mediated antiviral defense via ATG16L1/WIPI2B interaction for norovirus control, and circIPO7 was found to competitively block CAPRIN1–G3BP1 binding to suppress translation of EGFR/mTOR mRNAs.","evidence":"Co-IP, viral replication assays, IFN-γ treatment (norovirus); RNA pull-down, polysome fractionation, competition assays (circIPO7)","pmids":["37052473","36732659"],"confidence":"Medium","gaps":["Whether CAPRIN1 is a direct autophagy receptor or acts indirectly through ATG16L1 not resolved","Generalizability of circRNA-mediated CAPRIN1 regulation beyond specific cancer contexts not established"]},{"year":2025,"claim":"NMR studies of client partitioning into CAPRIN1 condensates showed that FUS RRM is recruited through arginine/aromatic contacts that are abolished by CAPRIN1 tyrosine phosphorylation, establishing a phospho-switch for client selectivity; WDR45 was identified as a stress granule disassembly factor that displaces G3BP1 from CAPRIN1.","evidence":"Solution NMR (HSQC, intermolecular NOE, PRE) in condensed phase; co-IP, competitive binding, iPSC-derived neurons from BPAN patients","pmids":["40857360","40473629"],"confidence":"High","gaps":["In vivo phosphorylation dynamics on CAPRIN1 condensate client selectivity not measured","Whether WDR45-mediated SG disassembly is CAPRIN1-dependent in all cell types unknown"]},{"year":2026,"claim":"CAPRIN1 was found to stabilize G-quadruplex structures in STAT1 mRNA 5'UTR to suppress translation, providing a structural mechanism for its translational repression activity and linking it to HBV-driven interferon resistance.","evidence":"RIP-MS, EMSA, ribosome profiling, circular dichroism, luciferase reporters, in vivo KD","pmids":["41951358"],"confidence":"Medium","gaps":["Whether rG4 stabilization is a general mechanism for all CAPRIN1-repressed mRNAs not tested","Direct structural visualization of CAPRIN1 bound to rG4 not achieved"]},{"year":null,"claim":"A full structural model of the CAPRIN1–G3BP1–FMRP ternary complex on RNA, the identity of kinases and phosphatases controlling CAPRIN1 phase separation in vivo, and the rules determining mRNA target selectivity remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length structure of CAPRIN1 or ternary complex","Kinases/phosphatases for CAPRIN1 tyrosine and serine phosphorylation in vivo not identified","Comprehensive rules for mRNA target selectivity (sequence/structure features) not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,7,14,26,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,12,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,3,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,25,26]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,14,17,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,26,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,11]}],"complexes":["G3BP1-CAPRIN1-USP10 stress granule complex","CAPRIN1-FMRP neuronal RNP complex","G3BP1-CAPRIN1-PKR innate immune complex"],"partners":["G3BP1","FMRP","PKR","USP10","XRN2","SPOP","WDR45","METTL3"],"other_free_text":[]},"mechanistic_narrative":"CAPRIN1 is a cytoplasmic RNA-binding phosphoprotein that functions as a central scaffold for stress granule assembly and mRNA translational regulation, with roles spanning cell proliferation, innate antiviral immunity, and synaptic plasticity. Its C-terminal RGG motifs selectively bind specific mRNAs (c-Myc, cyclin D2, STAT1, NCOA4) to repress or promote their translation, while its N-terminal GIM motif binds the NTF2-like domain of G3BP1 in a mutually exclusive manner with USP10, thereby tuning stress granule condensation [PMID:17210633, PMID:27022092, PMID:36279435]. CAPRIN1 undergoes liquid–liquid phase separation driven by arginine- and aromatic-rich intrinsically disordered region interactions that are modulated by phosphorylation, O-GlcNAcylation, ATP, and noncoding RNAs, and these condensates serve as platforms for translational repression, client protein recruitment, and RNA degradation via XRN2 [PMID:31439799, PMID:34074792, PMID:36040869, PMID:36495875]. In neurons, CAPRIN1 is essential for dendritic mRNA localization governing Na⁺/K⁺-ATPase function, AMPA receptor scaling, and long-term memory formation, while in innate immunity it activates PKR and promotes interferon-stimulated gene translation [PMID:20861386, PMID:29157358, PMID:25784705, PMID:24992036]."},"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 Classified","n_dependent_lines":112,"n_total_lines":1208,"dependency_fraction":0.09271523178807947},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000135387","cell_line_id":"CID001511","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"RPLP0;RPLP0P6","stoichiometry":10.0},{"gene":"RPLP2","stoichiometry":10.0},{"gene":"RPLP1","stoichiometry":10.0},{"gene":"RPL21","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL13A;RPL13A","stoichiometry":10.0},{"gene":"RPS19","stoichiometry":10.0},{"gene":"RPS2","stoichiometry":10.0},{"gene":"RPS12","stoichiometry":10.0},{"gene":"RPS3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001511","total_profiled":1310},"omim":[{"mim_id":"621353","title":"GLUTAMINE INSUFFICIENCY REGULATOR OF GLUTAMINASE LONG NONCODING RNA; GIRGL","url":"https://www.omim.org/entry/621353"},{"mim_id":"620782","title":"NEURODEVELOPMENTAL DISORDER 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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crystallographica. 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associated with microtubules at the leading/trailing edges of migrating cells.\",\n      \"method\": \"Mutagenesis of GIM motif and RGG motifs, co-immunoprecipitation, RNA-binding assays, immunofluorescence/live imaging, eIF2α phosphorylation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (mutagenesis, co-IP, RNA pulldown, functional assays) in a single foundational study\",\n      \"pmids\": [\"17210633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAPRIN1 is required for normal G1-S cell cycle progression; homozygous disruption of caprin-1 in DT40 cells markedly reduces proliferation rate due to prolongation of G1 phase, demonstrating an essential role in cellular proliferation.\",\n      \"method\": \"Homologous recombination knockout in DT40 cells, conditional expression rescue, cell cycle analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cell cycle phenotype and conditional rescue confirming specificity\",\n      \"pmids\": [\"16177067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAPRIN1 and USP10 bind mutually exclusively to the NTF2-like domain of G3BP1; Caprin1 binding promotes SG formation while USP10 binding inhibits it; G3BP1-F33W mutant (unable to bind Caprin1 or USP10) still rescues SG formation, indicating Caprin1/USP10 modulate rather than absolutely require G3BP1 for SG condensation; G3BP interacts with 40S ribosomal subunits through its RGG motif.\",\n      \"method\": \"G3BP1/2 double knockout cells, rescue with G3BP1 phosphomimetic/binding mutants, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic and biochemical dissection in DKO cells with multiple mutants, replicated findings\",\n      \"pmids\": [\"27022092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CAPRIN1 directly interacts with PKR (double-stranded RNA-dependent protein kinase) and forms a G3BP1-Caprin1-PKR complex; Caprin1 regulates efficient PKR activation at stress granules and is required for release of active PKR into the cytoplasm for substrate recognition; this complex is important for antiviral activity during mengovirus infection.\",\n      \"method\": \"Direct binding assays, co-immunoprecipitation, mengovirus infection model, PKR activity assays, SG localization studies\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction established with multiple biochemical methods plus functional viral infection readout\",\n      \"pmids\": [\"25784705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phase separation of CAPRIN1 and FMRP C-terminal intrinsically disordered regions is driven by arginine-rich and aromatic-rich region interactions; different phosphorylation patterns (FMRP serine/threonine, CAPRIN1 tyrosine) control phase separation propensity and modulate deadenylation and translation rates within condensates in vitro.\",\n      \"method\": \"NMR spectroscopy of condensed phases, phosphomimetic mutagenesis, in vitro deadenylation and translation assays, liquid-liquid phase separation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural data combined with mutagenesis and in vitro enzymatic reconstitution\",\n      \"pmids\": [\"31439799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CAPRIN1 (along with G3BP1 and G3BP2) is required for translation of interferon-stimulated gene (ISG) mRNAs including PKR and IFITM2; dengue virus sfRNA binds to CAPRIN1 (and G3BP1/2) to sequester them, inhibiting ISG mRNA translation as an immune evasion mechanism.\",\n      \"method\": \"siRNA knockdown, polysome profiling, RNA immunoprecipitation, viral infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined translational phenotype plus viral RNA binding assays\",\n      \"pmids\": [\"24992036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Japanese encephalitis virus (JEV) core protein interacts with CAPRIN1 (identified by affinity capture mass spectrometry); residues Lys97 and Arg98 in the JEV core protein α-helix are critical for Caprin-1 binding; this interaction inhibits stress granule formation and facilitates viral propagation and virulence in mice.\",\n      \"method\": \"Affinity capture mass spectrometry, alanine scanning mutagenesis, mutant virus infection assays, in vivo mouse virulence model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — MS identification plus mutagenesis with in vitro and in vivo functional validation\",\n      \"pmids\": [\"23097442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CAPRIN1 interacts with FMRP in neuronal ribonucleoprotein complexes; they co-associate with mRNAs including CaMKIIα and Map1b; the complex is present in polysomes and neuronal trafficking granules, suggesting CAPRIN1 modulates FMRP-dependent translation regulation.\",\n      \"method\": \"Immunoprecipitation with monoclonal and chicken antibodies, in vitro binding, polysome fractionation, neuronal granule co-localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and in vitro binding with fractionation, single laboratory\",\n      \"pmids\": [\"22737234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of a CAPRIN1 fragment (residues 132–251) reveals a novel all-α-helical fold that mediates homodimerization; dimerization creates a large negatively charged concave surface that functions as a protein-binding groove for partners including FMRP; the FMRP-interacting motif forms an integral helix that does not disrupt dimerization; structural basis for an RNP complex of Caprin1-FMRP-G3BP1 is proposed.\",\n      \"method\": \"X-ray crystallography, structural analysis, biochemical binding data integration\",\n      \"journal\": \"Acta crystallographica Section D\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis-guided interpretation and integration with existing biochemical data\",\n      \"pmids\": [\"27303792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMR studies of condensed CAPRIN1 C-terminal IDR (residues 607–709) identify specific side-chain and backbone interactions driving phase separation; ATP interactions with CAPRIN1 can enhance or reduce phase separation; O-GlcNAcylation of specific residues reduces phase separation propensity; arginine-containing N-terminal region is critical for phase separation relative to other Arg-rich stretches.\",\n      \"method\": \"NMR spectroscopy of condensed phase, mutagenesis, ATP titration, O-GlcNAcylation studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution NMR with mutagenesis validation, multiple orthogonal approaches\",\n      \"pmids\": [\"34074792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNG105 (Caprin1/mouse ortholog) knock-out in mice reduces dendritic localization of mRNAs encoding Na+/K+ ATPase subunit isoforms (α3, FXYD1, FXYD6, FXYD7), leading to loss of NKA function in dendrites without affecting somatic NKA; this impairs synapse formation and neuronal network maintenance.\",\n      \"method\": \"Caprin1 knockout mice, subcellular mRNA fractionation, electrophysiology, synapse morphology analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined mRNA localization and functional synaptic phenotype\",\n      \"pmids\": [\"20861386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNG105/Caprin1 deletion in mice causes severe deficits in long-term memory formation in spatial and contextual tasks; genome-wide mRNA profiling revealed RNG105 deficiency impairs asymmetric somato-dendritic localization of mRNAs including those encoding regulators of AMPAR surface expression; this is associated with attenuated homeostatic AMPAR scaling and reduced synaptic strength.\",\n      \"method\": \"Caprin1 KO mice, behavioral testing, genome-wide mRNA distribution profiling (hippocampus), electrophysiology, AMPAR surface expression assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined behavioral, molecular, and electrophysiological phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"29157358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of G3BP1-NTF2 domain in complex with Caprin-1-derived short linear motif (SLiM) shows Caprin-1 interacts with His-31 and His-62 within a third NTF2-binding site distinct from USP10's sites; G3BP1-NTF2 thermal stability is reduced at acidic pH and is counterbalanced better by USP10 than Caprin-1; acidification of condensates by ~0.5 pH units detected by ratiometric fluorescence; Caprin-1 N-terminal GIM suppresses G3BP1 LLPS while Caprin-1 C-terminal domain promotes LLPS, creating 'yin and yang' regulation of SG formation.\",\n      \"method\": \"X-ray crystallography, nano-differential scanning fluorimetry, biochemical binding assays, live cell ratiometric fluorescence (pHluorin2-G3BP1), in vitro LLPS assays\",\n      \"journal\": \"Open biology / Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — crystal structures from two independent studies combined with LLPS functional dissection and live cell measurements\",\n      \"pmids\": [\"37161291\", \"36279435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wild-type SPOP (E3 ubiquitin ligase adaptor) recognizes CAPRIN1 and triggers its ubiquitin-dependent degradation; prostate cancer-associated SPOP mutants fail to degrade CAPRIN1, leading to elevated CAPRIN1 and aberrant stress granule assembly; this confers resistance to docetaxel and other SG inducers in prostate cancer cells.\",\n      \"method\": \"Yeast two-hybrid identification, co-immunoprecipitation, ubiquitination assays, SPOP mutant expression, xenograft models, patient specimen analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — SPOP-CAPRIN1 interaction established biochemically with functional ubiquitination and in vivo xenograft validation\",\n      \"pmids\": [\"31771591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CAPRIN1 knockout in mouse ESCs significantly alters differentiation and gene expression programs; CAPRIN1 associates with thousands of RNA transcripts (by RIP-seq) and promotes their degradation via interaction with the ribonuclease XRN2; upon early ESC differentiation, XRN2 localizes to the nucleus and co-localizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner.\",\n      \"method\": \"CAPRIN1 KO in mouse ESCs, RIP-seq, SLAM-seq (metabolic RNA labeling), immunoprecipitation/mass spectrometry interactome, immunofluorescence co-localization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype combined with transcriptome-wide RIP-seq and interactome identifying XRN2 as functional partner\",\n      \"pmids\": [\"36495875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Caprin-1 interacts with Cyr61 (extracellular matrix protein); stable ectopic expression of Caprin-1 leads to stress granules containing both Caprin-1 and Cyr61, constitutive phosphorylation of Akt and ERK1/2, resistance to cisplatin-induced apoptosis, and dramatically enhanced tumor growth and lung metastasis in osteosarcoma xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, ectopic expression, xenograft mouse models, phospho-western blotting\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional in vivo xenograft data; pathway placement (Akt/ERK) by western blot only\",\n      \"pmids\": [\"23528710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Caprin-1 protein interactome (by endogenous IP-MS) in stressed and unstressed conditions identifies 1543 interacting proteins; stress-induced interactors include ribosome, spliceosome, and RNA transport pathway proteins; novel SG components ANKHD1, TALIN-1, GEMIN5, and SNRNP200 were validated as Caprin-1 stress-induced interactors localizing to arsenite-induced stress granules.\",\n      \"method\": \"Immunoprecipitation coupled with mass spectrometry, validation by co-IP and immunofluorescence in multiple cell lines\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — large-scale MS interactome with validation of selected hits; single laboratory\",\n      \"pmids\": [\"33939924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAPRIN1 promotes liquid-liquid phase separation when bound by the lncRNA GIRGL; GIRGL drives formation of a complex between CAPRIN1 dimers and GLS1 mRNA, inducing stress granule formation and translational suppression of GLS1 (glutaminase-1) mRNA under glutamine deprivation.\",\n      \"method\": \"RIP assay, LLPS assays, RNA-FISH, CAPRIN1 knockdown/overexpression, translational reporter assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple methods in a single laboratory establishing CAPRIN1-lncRNA-mRNA complex driving phase separation\",\n      \"pmids\": [\"33762340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circVAMP3 drives phase separation of CAPRIN1 and promotes stress granule formation; this suppresses c-Myc mRNA translation, reducing c-Myc protein levels and inhibiting HCC cell proliferation and metastasis in vitro and in vivo.\",\n      \"method\": \"circRNA overexpression, LLPS assays, stress granule imaging, polysome profiling, translation reporter assays, xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — circRNA-CAPRIN1 phase separation with defined translational consequence, single laboratory\",\n      \"pmids\": [\"35072355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX3X helicase physically interacts and co-localizes with CAPRIN1 and poly(A)-binding protein 1 (PABP1) at the leading edge of spreading fibroblasts; depletion of DDX3X leads to decreased cell motility, providing a functional link between DDX3X, Caprin-1, and initiation factors at the leading edge to promote cell migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, DDX3X depletion with cell motility/spreading assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and co-localization with functional KD phenotype; single laboratory, modest follow-up on CAPRIN1's specific contribution\",\n      \"pmids\": [\"28733330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NMR measurement of per-residue near-surface electrostatic potentials of the positively charged C-terminal IDR of CAPRIN1 along ATP-induced phase separation reveals that electrostatic shielding by ATP decreases surface potentials, promotes interchain interactions between aromatic-rich and arginine-rich regions, and drives phase separation; at high ATP, CAPRIN1 becomes negatively charged and re-enters the mixed phase.\",\n      \"method\": \"Solution NMR (paramagnetic relaxation enhancement, chemical shift perturbation), ATP titration, phase separation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic resolution NMR along phase separation trajectory with mechanistic model validated by multiple measurements\",\n      \"pmids\": [\"36040869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAPRIN1 interacts with ATG16L1 and WIPI2B to mediate LC3 targeting of murine norovirus (MNV) replication complexes; IFN-γ-mediated control of MNV replication is dependent on CAPRIN1.\",\n      \"method\": \"Co-immunoprecipitation, CAPRIN1 depletion in viral replication assays, IFN-γ treatment experiments\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — interaction identified with co-IP and confirmed by loss-of-function with viral replication readout; single laboratory\",\n      \"pmids\": [\"37052473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAPRIN1 condensates shift the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble; key contacts are between CAPRIN1 arginine-rich/aromatic-rich regions and the H80-H120 region of unfolded SOD1; unfolding of immature SOD1 in the CAPRIN1 condensed phase is coupled to aggregation.\",\n      \"method\": \"Solution NMR spectroscopy (mixed phase and demixed CAPRIN1 condensates), intermolecular NOE, PRE experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution NMR in condensed phase with mechanistic mapping of interaction sites\",\n      \"pmids\": [\"39172789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CAPRIN1-P512L de novo missense variant causes aberrant protein aggregation; overexpressed CAPRIN1-P512L forms insoluble ubiquitinated aggregates sequestering ATXN2, GEMIN5, SNRNP200, and SNCA; iPSC-derived cortical neurons with this mutation show reduced neuronal activity, altered stress granule dynamics, and enhanced RNA-promoted aggregation in vitro.\",\n      \"method\": \"Protein solubility assays, co-aggregation by co-IP/western blot, iPSC-derived neuron electrophysiology, nano-DSF, stress granule dynamics imaging\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function mutation with multiple cellular and biochemical readouts; single laboratory\",\n      \"pmids\": [\"36136249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR45 forms gel-like condensates via its WD5 domain and 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, phase separation assays, competitive binding assays, iPSC-derived midbrain neurons from BPAN patient, stress granule dynamics imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of WDR45-Caprin1 interaction with patient-derived neuron validation; single laboratory\",\n      \"pmids\": [\"40473629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPRIN1 interacts with METTL3 and regulates m6A modification of RIG-I mRNA; this interaction and m6A regulatory activity occurs within cellular stress granules; CAPRIN1 modulates interferon-associated gene networks and M. tuberculosis infection responses.\",\n      \"method\": \"Co-immunoprecipitation with METTL3, m6A-RIP, stress granule localization studies, CAPRIN1 knockdown in infection models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — novel interaction with defined m6A writer established by co-IP and RIP; single laboratory, emerging mechanism\",\n      \"pmids\": [\"41198861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAPRIN1 stabilizes the G-quadruplex (rG4) structure in the 5'UTR of STAT1 mRNA, halting ribosomal scanning and suppressing STAT1 protein translation; CAPRIN1 interacts with STAT1 rG4 (demonstrated by EMSA, luciferase reporter, and ribosome profiling); HBV polymerase functions as a transcription factor driving CAPRIN1 expression, causing IFN resistance.\",\n      \"method\": \"RIP-mass spectrometry, EMSA, luciferase reporter assays, ribosome profiling, circular dichroism, CAPRIN1 knockdown in vitro and in vivo\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EMSA, ribosome profiling, RIP-MS) establishing rG4 binding and translational repression; single laboratory\",\n      \"pmids\": [\"41951358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circIPO7 directly binds Caprin-1 at sites overlapping with the G3BP1-binding region, blocking the Caprin-1–G3BP1 interaction and dissociating Caprin-1 and its target mRNAs (EGFR and mTOR mRNAs) from ribosomes, resulting in their translational inhibition and PI3K/AKT/mTOR pathway inactivation in gastric cancer.\",\n      \"method\": \"RNA pull-down, RIP assay, polysome fractionation, co-immunoprecipitation competition assays, cell proliferation assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNA-protein interaction mapped by pull-down/RIP with defined translational and signaling consequences; single laboratory\",\n      \"pmids\": [\"36732659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CAPRIN1 interacts with ULK1 and STK38, manipulating ULK1 phosphorylation to activate autophagy and promote tumor growth in pancreatic cancer.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, loss-of-function studies with autophagy readout, xenograft models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with phosphorylation assay; pathway placement indirect; single laboratory\",\n      \"pmids\": [\"38082307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAPRIN1 mediates sorafenib resistance in hepatocellular carcinoma by interacting with NCOA4 mRNA via its RGG domain and recruiting NCOA4 mRNA into stress granules, repressing NCOA4 translation and blunting sorafenib-induced ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, RIP assay, stress granule imaging, translation reporter, CAPRIN1 KO rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RGG-domain-specific RNA interaction with translational and functional consequences; single laboratory\",\n      \"pmids\": [\"41896589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10 promotes ac4C (N4-acetylcytidine) modification of CAPRIN1 mRNA, stabilizing it and increasing CAPRIN1 protein expression; NAT10 knockdown reduces ac4C levels on CAPRIN1 mRNA and decreases its stability.\",\n      \"method\": \"ac4C-RIP, actinomycin D mRNA stability assay, NAT10 knockdown, CAPRIN1 overexpression rescue\",\n      \"journal\": \"BMC women's health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNA modification writer identified with stability assay; established ac4C-RIP; single laboratory\",\n      \"pmids\": [\"39923057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAPRIN1 NMR studies in CAPRIN1 condensates reveal that FUS RRM (a client) partitions 30-fold into CAPRIN1 condensates via interactions between FUS RRM and aromatic-rich and arginine-rich regions of CAPRIN1; tyrosine phosphorylation of CAPRIN1 disrupts these interactions and reduces client partitioning by over 100-fold.\",\n      \"method\": \"Solution NMR (HSQC, intermolecular NOE, PRE), chemical shift perturbation in mixed/demixed phases\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution NMR mapping of client-scaffold interactions within condensates, with PTM effect validated\",\n      \"pmids\": [\"40857360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAPRIN1 is a cytoplasmic RNA-binding phosphoprotein that forms an RNP complex with G3BP1 and FMRP; it selectively binds specific mRNAs (c-Myc, cyclin D2, STAT1) via its C-terminal RGG motifs to regulate their translation, recruits PKR for antiviral innate immune activation, drives liquid-liquid phase separation via arginine/aromatic-rich IDR interactions that are tuned by phosphorylation and ATP, undergoes ubiquitin-dependent degradation by SPOP (opposing its SG-promoting activity), mediates dendritic mRNA localization essential for synaptic plasticity and long-term memory, and promotes RNA degradation during ESC differentiation through interaction with XRN2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CAPRIN1 is a cytoplasmic RNA-binding phosphoprotein that functions as a central scaffold for stress granule assembly and mRNA translational regulation, with roles spanning cell proliferation, innate antiviral immunity, and synaptic plasticity. Its C-terminal RGG motifs selectively bind specific mRNAs (c-Myc, cyclin D2, STAT1, NCOA4) to repress or promote their translation, while its N-terminal GIM motif binds the NTF2-like domain of G3BP1 in a mutually exclusive manner with USP10, thereby tuning stress granule condensation [PMID:17210633, PMID:27022092, PMID:36279435]. CAPRIN1 undergoes liquid–liquid phase separation driven by arginine- and aromatic-rich intrinsically disordered region interactions that are modulated by phosphorylation, O-GlcNAcylation, ATP, and noncoding RNAs, and these condensates serve as platforms for translational repression, client protein recruitment, and RNA degradation via XRN2 [PMID:31439799, PMID:34074792, PMID:36040869, PMID:36495875]. In neurons, CAPRIN1 is essential for dendritic mRNA localization governing Na⁺/K⁺-ATPase function, AMPA receptor scaling, and long-term memory formation, while in innate immunity it activates PKR and promotes interferon-stimulated gene translation [PMID:20861386, PMID:29157358, PMID:25784705, PMID:24992036].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that CAPRIN1 is required for cell proliferation answered whether the gene has a cell-autonomous growth function, revealing it as essential for G1-to-S progression.\",\n      \"evidence\": \"Homologous recombination knockout in DT40 cells with conditional rescue and cell cycle analysis\",\n      \"pmids\": [\"16177067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of G1-S promotion unknown — target mRNAs not yet identified\", \"No mammalian in vivo proliferation data at this point\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of the G3BP1-binding GIM motif and the RNA-binding RGG motifs defined CAPRIN1 as a modular RNA-granule scaffold that selectively binds c-Myc and cyclin D2 mRNAs and induces stress granule formation via eIF2α phosphorylation.\",\n      \"evidence\": \"Mutagenesis of GIM and RGG motifs, co-IP, RNA-binding assays, eIF2α phosphorylation, immunofluorescence\",\n      \"pmids\": [\"17210633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GIM–NTF2 interaction unresolved\", \"Mechanism linking CAPRIN1 overexpression to eIF2α phosphorylation not delineated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout mice revealed that CAPRIN1 controls dendritic mRNA localization of Na⁺/K⁺-ATPase subunit transcripts, establishing its role in neuronal compartment-specific translation and synapse maintenance.\",\n      \"evidence\": \"Caprin1 KO mice with subcellular mRNA fractionation, electrophysiology, synapse morphology\",\n      \"pmids\": [\"20861386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAPRIN1 directly transports these mRNAs or acts indirectly through granule partners not resolved\", \"Behavioral consequences not yet tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that CAPRIN1 interacts with FMRP in neuronal RNP complexes on polysomes, and that viral core proteins (JEV) hijack CAPRIN1 to suppress stress granules, established CAPRIN1 as both a neuronal translational regulator and a viral target.\",\n      \"evidence\": \"Co-IP/in vitro binding with polysome fractionation (FMRP); affinity-capture MS with mutagenesis and in vivo virulence (JEV)\",\n      \"pmids\": [\"22737234\", \"23097442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CAPRIN1–FMRP interaction unknown\", \"Whether FMRP and G3BP1 bind CAPRIN1 simultaneously or competitively not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that CAPRIN1/G3BP1/G3BP2 are required for ISG mRNA translation, and that dengue sfRNA sequesters them, revealed CAPRIN1 as a positive translational regulator of innate immune transcripts and a target of viral immune evasion.\",\n      \"evidence\": \"siRNA knockdown, polysome profiling, RNA immunoprecipitation, dengue infection assays\",\n      \"pmids\": [\"24992036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAPRIN1 directly loads ISG mRNAs onto ribosomes or acts via G3BP unclear\", \"Breadth of ISG mRNA targets not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of a G3BP1–CAPRIN1–PKR complex that activates PKR at stress granules and releases it for antiviral signaling established CAPRIN1 as a platform for innate immune kinase activation.\",\n      \"evidence\": \"Direct binding assays, co-IP, PKR activity assays, mengovirus infection model\",\n      \"pmids\": [\"25784705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAPRIN1 allosterically activates PKR or merely concentrates it in granules not distinguished\", \"Generalizability beyond mengovirus not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural and genetic dissection showed that CAPRIN1 and USP10 compete for the same G3BP1-NTF2 surface with opposing effects on stress granule condensation, and that CAPRIN1 homodimerizes via a novel α-helical fold creating a binding groove for FMRP.\",\n      \"evidence\": \"G3BP1/2 DKO rescue with mutants; X-ray crystallography of CAPRIN1 fragment (residues 132–251)\",\n      \"pmids\": [\"27022092\", \"27303792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structure of CAPRIN1–G3BP1–FMRP ternary complex not determined\", \"How CAPRIN1 dimerization affects RNA binding not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Caprin1 KO mice showed severe long-term memory deficits with impaired dendritic mRNA asymmetry and attenuated AMPA receptor homeostatic scaling, establishing CAPRIN1 as essential for synaptic plasticity and cognitive function.\",\n      \"evidence\": \"KO mice, behavioral testing, genome-wide mRNA profiling, electrophysiology, AMPAR surface expression\",\n      \"pmids\": [\"29157358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the memory deficit is cell-autonomous to excitatory neurons not resolved\", \"Contribution of individual CAPRIN1-dependent mRNAs to the phenotype not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NMR and phosphomimetic studies revealed that CAPRIN1 C-terminal IDR phase separation is driven by arginine–aromatic interactions and tuned by differential phosphorylation, providing the biophysical basis for stress granule condensation; separately, SPOP was identified as the E3 ligase adaptor mediating CAPRIN1 ubiquitin-dependent degradation, with cancer-associated SPOP mutants stabilizing CAPRIN1 and promoting aberrant SG assembly.\",\n      \"evidence\": \"NMR of condensed phases, phosphomimetic mutagenesis, in vitro deadenylation/translation (phase separation); yeast two-hybrid, ubiquitination assays, xenograft models (SPOP)\",\n      \"pmids\": [\"31439799\", \"31771591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which kinases phosphorylate CAPRIN1 tyrosines in vivo not identified\", \"Whether SPOP-mediated degradation occurs at stress granules or in the soluble phase unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Atomic-resolution NMR mapped specific side-chain contacts driving CAPRIN1 phase separation and showed that ATP and O-GlcNAcylation bidirectionally modulate condensation, while noncoding RNAs (lncRNA GIRGL) were found to promote CAPRIN1 LLPS and translational repression of specific mRNAs.\",\n      \"evidence\": \"NMR with mutagenesis and ATP/O-GlcNAc titrations; RIP, LLPS assays, translational reporters for GIRGL\",\n      \"pmids\": [\"34074792\", \"33762340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo O-GlcNAcylation stoichiometry on CAPRIN1 not determined\", \"How lncRNA binding remodels CAPRIN1 IDR conformation not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Crystal structures of G3BP1-NTF2 with Caprin-1 SLiM revealed a distinct binding site (His-31/His-62), and functional studies demonstrated that CAPRIN1's N-terminal GIM suppresses while its C-terminal domain promotes LLPS, establishing 'yin-and-yang' regulation; separately, CAPRIN1 was shown to promote RNA degradation via XRN2 in ESC differentiation, and a disease-linked P512L variant caused aberrant aggregation with sequestration of neurodegeneration-associated proteins.\",\n      \"evidence\": \"X-ray crystallography, nano-DSF, LLPS assays, ratiometric fluorescence (G3BP1-NTF2); CAPRIN1 KO ESCs, RIP-seq, SLAM-seq (XRN2); iPSC-derived neurons, solubility assays (P512L)\",\n      \"pmids\": [\"36279435\", \"37161291\", \"36495875\", \"36136249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pH-dependent SG regulation via His residues operates in physiological stress not tested in vivo\", \"XRN2 recruitment mechanism to CAPRIN1 granules not structurally defined\", \"P512L disease causality in humans requires genetic replication\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CAPRIN1 was linked to autophagy-mediated antiviral defense via ATG16L1/WIPI2B interaction for norovirus control, and circIPO7 was found to competitively block CAPRIN1–G3BP1 binding to suppress translation of EGFR/mTOR mRNAs.\",\n      \"evidence\": \"Co-IP, viral replication assays, IFN-γ treatment (norovirus); RNA pull-down, polysome fractionation, competition assays (circIPO7)\",\n      \"pmids\": [\"37052473\", \"36732659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CAPRIN1 is a direct autophagy receptor or acts indirectly through ATG16L1 not resolved\", \"Generalizability of circRNA-mediated CAPRIN1 regulation beyond specific cancer contexts not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"NMR studies of client partitioning into CAPRIN1 condensates showed that FUS RRM is recruited through arginine/aromatic contacts that are abolished by CAPRIN1 tyrosine phosphorylation, establishing a phospho-switch for client selectivity; WDR45 was identified as a stress granule disassembly factor that displaces G3BP1 from CAPRIN1.\",\n      \"evidence\": \"Solution NMR (HSQC, intermolecular NOE, PRE) in condensed phase; co-IP, competitive binding, iPSC-derived neurons from BPAN patients\",\n      \"pmids\": [\"40857360\", \"40473629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo phosphorylation dynamics on CAPRIN1 condensate client selectivity not measured\", \"Whether WDR45-mediated SG disassembly is CAPRIN1-dependent in all cell types unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"CAPRIN1 was found to stabilize G-quadruplex structures in STAT1 mRNA 5'UTR to suppress translation, providing a structural mechanism for its translational repression activity and linking it to HBV-driven interferon resistance.\",\n      \"evidence\": \"RIP-MS, EMSA, ribosome profiling, circular dichroism, luciferase reporters, in vivo KD\",\n      \"pmids\": [\"41951358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether rG4 stabilization is a general mechanism for all CAPRIN1-repressed mRNAs not tested\", \"Direct structural visualization of CAPRIN1 bound to rG4 not achieved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full structural model of the CAPRIN1–G3BP1–FMRP ternary complex on RNA, the identity of kinases and phosphatases controlling CAPRIN1 phase separation in vivo, and the rules determining mRNA target selectivity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure of CAPRIN1 or ternary complex\", \"Kinases/phosphatases for CAPRIN1 tyrosine and serine phosphorylation in vivo not identified\", \"Comprehensive rules for mRNA target selectivity (sequence/structure features) not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 7, 14, 26, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 12, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 3, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074391\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 25, 26]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 14, 17, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 26, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\n      \"G3BP1-CAPRIN1-USP10 stress granule complex\",\n      \"CAPRIN1-FMRP neuronal RNP complex\",\n      \"G3BP1-CAPRIN1-PKR innate immune complex\"\n    ],\n    \"partners\": [\n      \"G3BP1\",\n      \"FMRP\",\n      \"PKR\",\n      \"USP10\",\n      \"XRN2\",\n      \"SPOP\",\n      \"WDR45\",\n      \"METTL3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}