{"gene":"LARP4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2017,"finding":"LARP4 binds poly(A) RNA and poly(A)-binding protein (PABP), and its PABP-interaction domain and RNA-binding module are required for net lengthening of poly(A) tails (PATs) of heterologous mRNAs including ribosomal protein (RP) mRNAs, with concomitant mRNA stabilization. Genetic deletion of LARP4 decreases PAT length and RP mRNA stability. The RNA-binding module is sensitive to poly(A) 3'-termini, consistent with protection from deadenylation.","method":"Genetic knockout, overexpression, PAT-seq, domain mutagenesis, in-cell assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, OE, domain mutagenesis, PAT-seq) in a single rigorous study with clear mechanistic readouts","pmids":["28895529"],"is_preprint":false},{"year":2015,"finding":"LARP4 mRNA 3'UTR contains a conserved AU-rich element (ARE) that destabilizes mRNA. Tristetraprolin (TTP) binds LARP4 mRNA in vivo and decreases cellular LARP4 levels; TTP knockout cells accumulate higher LARP4. TNF-α stimulation induces a TTP pulse that causes a transient decrease in LARP4 mRNA and protein, establishing LARP4 as a target of TNF-α–TTP post-transcriptional regulation.","method":"β-globin reporter stability assay, RNA co-immunoprecipitation, TTP gene knockout mouse cells, TNF-α stimulation","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, KO cells, reporter assay, and cytokine stimulation time-course, multiple orthogonal methods in one study","pmids":["26644407"],"is_preprint":false},{"year":2020,"finding":"Single-molecule PAT-seq (SM-PAT-seq) transcriptome-wide analysis in LARP4 knockout versus control cells shows LARP4 opposes deadenylation throughout mRNA lifespan, with greatest impact at short poly(A) tails of 30–75 nucleotides. Accelerated deadenylation in KO cells at PATs <75 nt is consistent with greater PABP dissociation in the absence of LARP4.","method":"SM-PAT-seq (single-molecule nucleotide-resolution transcriptome-wide poly(A) tail sequencing), LARP4 knockout cells, time-course PAT decay analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide single-molecule method in KO cells with time-course analysis, replicating and extending prior mechanistic findings","pmids":["32744499"],"is_preprint":false},{"year":2016,"finding":"LARP4 depletion in PC3 and MDA-MB-231 cancer cells increases cell migration, invasion, and invasive protrusions in 3D Matrigel. Overexpression reduces cell elongation. A cancer-associated truncation mutant shows enhanced interaction with PABP and enhanced effects on cell morphology, establishing LARP4 as an inhibitor of cancer cell migration and invasion.","method":"RNAi depletion, overexpression, transwell migration/invasion assay, 3D Matrigel, Co-immunoprecipitation of PABP with truncation mutant","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — clean KD/OE with defined cellular phenotype and partial mechanistic follow-up (PABP interaction), single lab","pmids":["27615744"],"is_preprint":false},{"year":2020,"finding":"LARP4 knockout in mice destabilizes Nfκb1 mRNAs in CD4+ T cells and reduces secretion of IL-2 and IFN-γ upon T cell activation, placing LARP4 as a regulator of T cell activation-dependent mRNA stabilization.","method":"BruChase-Seq (transcriptome-wide nascent mRNA stability), Larp4 knockout mouse, cytokine secretion assay","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with transcriptome-wide stability assay and functional cytokine readout, single lab","pmids":["32735645"],"is_preprint":false},{"year":2021,"finding":"LARP4 directly binds poly(A) and PABP (PABPC1), contains a PAM2 motif that interacts with the MLLE domain of PABP, and opposes deadenylation by stabilizing PABP on mRNA poly(A) tails. LARP1 and LARP4 are described as sharing these activities to protect mRNA 3' poly(A) tails from deadenylases.","method":"Review/mechanistic synthesis of prior biochemical data; PAM2-MLLE interaction established by prior in vitro binding assays referenced therein","journal":"RNA Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic summary with supporting biochemical framework, but primarily a review consolidating prior experimental evidence","pmids":["33522422"],"is_preprint":false},{"year":2023,"finding":"LARP4 interacts with the mechanosensing immunoglobulin-like repeat 21 (R21) domain of Filamin A (FLNA) through a force-exposed cryptic binding site. The LARP4 region responsible maps to residues around position 277 (F277 in human). A F277A mutation disrupts FLNA binding. FRAP of GFP-LARP4 shows mutant LARP4 diffuses faster than WT. LARP4 knockdown increases cell migration speed, and expression of FLNA-binding-deficient LARP4 fails to rescue, establishing that LARP4–FLNA interaction regulates cell migration.","method":"Co-immunoprecipitation (in vivo and in vitro), FRAP, proximity ligation assay, site-directed mutagenesis, LARP4 knockdown, cell migration assay","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vivo/in vitro binding, mutagenesis, FRAP, and functional migration rescue assay, single lab","pmids":["37169020"],"is_preprint":false},{"year":2025,"finding":"The crystal structure of FLNA R21 in complex with the LARP4 peptide (residues Ala269–Asn281) was determined by X-ray crystallography, showing LARP4 forms an extended β strand that binds the cleft formed by β strands C and D of FLNA R21. The LARP4-binding site overlaps with the integrin β tail-binding region, and in vitro assays show LARP4 competes with integrin β7 tails for FLNA R21 binding. Cancer-associated A279Cfs*2 and experimental F277A mutations disrupt binding; N275S alters membrane localization without affecting FLNA binding.","method":"X-ray crystallography, protein-protein interaction assays, site-directed mutagenesis, cell migration assay, in vitro competition assay","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with mutagenesis and functional cell migration validation, single lab but multiple orthogonal methods","pmids":["40466905"],"is_preprint":false},{"year":2024,"finding":"LARP4's conserved region-2 (CR2; positions 615–625) directly binds RACK1 (a ribosome-associated protein) at RACK1 propellers 5 and 6 (residues 200–317), as established by yeast two-hybrid mapping, in vitro binding, AlphaFold2-Multimer prediction, and confirmed by CR2 mutations that abolish RACK1 and ribosome association. CR2 mutations reduce LARP4's ability to stabilize ARE-containing mRNAs and impair LARP4-mediated translational efficiency of ARE-mRNAs, while PABP association is less affected, indicating independent interactions.","method":"Yeast two-hybrid domain mapping, in vitro binding assay, AlphaFold2-Multimer structural prediction, site-directed mutagenesis, polysome profiling, luciferase reporter assay, Co-immunoprecipitation","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vitro reconstitution, structural prediction, mutagenesis, and functional translation assays in one rigorous study","pmids":["39898547"],"is_preprint":false},{"year":2024,"finding":"LARP4 preprint (same study as PMID 39898547): CR2 of LARP4 (positions 615–625) directly binds RACK1 region 200–317; CR2 mutations abolish RACK1/ribosome association without equally affecting PABP; LARP4 promotes translational efficiency of ARE-containing mRNAs via this CR2–RACK1 interaction.","method":"Yeast two-hybrid, in vitro binding, mutagenesis, polysome profiling, nanoLuc reporter assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — preprint version of peer-reviewed PMID 39898547; included only as it predates publication but is now superseded by the peer-reviewed paper","pmids":["39554137"],"is_preprint":true},{"year":2024,"finding":"LARP4 binds nuclear-encoded mitochondrial mRNAs (NEMmRNAs), particularly those encoding respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs). LARP4 depletion significantly reduces RCCP and MRP protein levels by quantitative proteomics and reduces mitochondrial function; LARP4 re-expression rescues mitochondrial respiratory function.","method":"CLIP-seq (systematic RBP-RNA target analysis across 150 RBPs), quantitative proteomics after LARP4 depletion, mitochondrial function assays, rescue by LARP4 re-expression","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — eCLIP/CLIP-based target identification plus quantitative proteomics and functional rescue, single lab","pmids":["38164626"],"is_preprint":false},{"year":2024,"finding":"PEDV coronavirus infection induces nuclear-to-cytoplasmic shuttling of LARP4 via a CRM1-independent pathway. Cytoplasmic LARP4 binds the 3'UTR of PEDV mRNA with assistance from PABPC1 to facilitate viral mRNA translation. LARP4 knockdown reduces PABPC1-induced 3'UTR translation activity. Purified prokaryotic LARP4 and PABPC1 together enhance PEDV mRNA translation in a rabbit reticulocyte lysate (RRL) system.","method":"Subcellular fractionation/localization, LARP4 knockdown, RRL in vitro translation assay, reporter assays","journal":"Veterinary Microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro translation reconstitution in RRL plus cell-based localization and KD experiments, single lab","pmids":["39182469"],"is_preprint":false},{"year":2025,"finding":"LARP4 drives hypertranslation in exhausted/dysfunctional intratumoral T cells by selectively enhancing translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion, and enhances anti-tumor effector persistence. LARP4 knockdown in CAR-T cells prevents terminal exhaustion.","method":"Conditional Larp4 knockout in T cells, translatome profiling, mitochondrial function assays, in vivo tumor models, CAR-T cell functional assays","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with translatome profiling, mitochondrial functional readouts, and in vivo anti-tumor efficacy, multiple orthogonal approaches","pmids":["40696044"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of LARP4 in naive CD4+ T cells enhances quiescence and dampens quiescence exit by altering stability of mRNAs important for T cell activation, impairing differentiation into helper T cell subsets. A peptide inhibitor of LARP4 (LIPEP) mimics LARP4 deficiency and ameliorates autoimmune and allergic responses in mouse models.","method":"Conditional knockout mouse, mRNA stability analysis, T cell differentiation assays, peptide inhibitor in vivo mouse disease models","journal":"Nature Biomedical Engineering","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with mRNA stability assays and in vivo disease rescue, multiple orthogonal methods","pmids":["41102557"],"is_preprint":false},{"year":2024,"finding":"LARP4 cooperates with TENT5C cytoplasmic poly(A) polymerase in erythropoiesis: LARP4/5 depletion leads to downregulation and poly(A) tail shortening of globin mRNAs. Proteomic experiments revealed a transient but specific association of TENT5C with LARP4/5. Lack of TENT5C catalytic activity is accompanied by compensatory upregulation of LARP4/5, indicating functional redundancy in protecting globin mRNA poly(A) tails.","method":"Proteomics (Co-AP/MS), poly(A) tail length sequencing, LARP4/5 depletion, TENT5C catalytic mutant knock-in mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with proteomic co-association, KO/depletion phenotype, and PAT-seq in a relevant primary cell context, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2024.11.14.623596"],"is_preprint":true},{"year":2017,"finding":"The LARP4 mRNA contains a translation-dependent coding region determinant (CRD) of instability comprising <10% of codons; synonymous substitutions accommodating tRNA dynamics cause >20-fold variation in LARP4 mRNA levels. Overexpression of the most limiting tRNA increases LARP4 protein levels, indicating LARP4 expression is controlled by codon-tRNA matching during translation.","method":"Synonymous codon substitution, tRNA overexpression, mRNA level measurement","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic synonymous codon substitution panel with tRNA manipulation, single lab, multiple genetic perturbations","pmids":["28895529"],"is_preprint":false}],"current_model":"LARP4 is a cytoplasmic RNA-binding protein that binds poly(A) RNA and poly(A)-binding protein (PABP) via a PAM2-MLLE interaction, protecting mRNA poly(A) tails from deadenylation throughout mRNA lifespan; it also interacts with ribosome-associated RACK1 through its conserved region-2 (CR2) to promote translational efficiency of specific mRNA subsets (including ARE-containing and OXPHOS mRNAs), interacts with Filamin A's mechanosensing R21 domain to regulate cell migration, is post-transcriptionally downregulated by the TTP–TNF-α axis, and plays key roles in T cell activation, quiescence, and exhaustion by modulating mRNA stability and translation."},"narrative":{"mechanistic_narrative":"LARP4 is a cytoplasmic RNA-binding protein that protects mRNA poly(A) tails from deadenylation and tunes the stability and translation of specific mRNA subsets [PMID:28895529, PMID:32744499]. It binds poly(A) RNA and poly(A)-binding protein (PABPC1) — engaging the PABP MLLE domain through its PAM2 motif — and its RNA-binding module, sensitive to poly(A) 3' termini, stabilizes PABP on tails to oppose deadenylation throughout mRNA lifespan, with the greatest effect on short tails of 30–75 nucleotides [PMID:28895529, PMID:32744499, PMID:33522422]. A second, PABP-independent activity is mediated by its conserved region-2 (CR2), which directly binds the ribosome-associated protein RACK1 at propellers 5–6; this interaction is required for LARP4 to stabilize and promote the translational efficiency of ARE-containing mRNAs [PMID:39898547]. Through these activities LARP4 supports translation of nuclear-encoded mitochondrial and oxidative phosphorylation mRNAs and respiratory chain function [PMID:38164626, PMID:40696044]. LARP4 also acts at the cytoskeleton, binding the force-exposed cryptic site in the mechanosensing R21 domain of Filamin A via a region around residue F277 — an interaction resolved at atomic resolution that overlaps the integrin β-tail site — and this LARP4–FLNA interaction restrains cell migration and invasion [PMID:27615744, PMID:37169020, PMID:40466905]. LARP4 abundance is itself controlled post-transcriptionally: an AU-rich element in its 3'UTR makes it a target of the TNF-α–tristetraprolin axis [PMID:26644407], and a translation-dependent codon-tRNA matching determinant in its coding region sets its expression level [PMID:28895529]. In T cells, LARP4 governs activation-dependent mRNA stabilization, quiescence exit, and exhaustion, with its loss restoring mitochondrial fitness and anti-tumor effector persistence [PMID:32735645, PMID:40696044, PMID:41102557].","teleology":[{"year":2015,"claim":"Established how LARP4 levels are themselves regulated, showing the RNA-stability machinery feeds back onto the regulator.","evidence":"β-globin reporter stability assay, RNA co-IP, TTP knockout cells, and TNF-α stimulation time-course","pmids":["26644407"],"confidence":"High","gaps":["Does not address LARP4's own molecular function on target mRNAs","Physiological consequence of the transient TNF-α-induced LARP4 dip not defined"]},{"year":2017,"claim":"Defined LARP4's core biochemical activity: binding poly(A) and PABP to lengthen and stabilize mRNA poly(A) tails, answering what LARP4 does to mRNA.","evidence":"Genetic knockout, overexpression, PAT-seq, and domain mutagenesis with in-cell assays","pmids":["28895529"],"confidence":"High","gaps":["Transcriptome-wide kinetics and tail-length dependence not yet resolved","Translation-level consequences not addressed"]},{"year":2017,"claim":"Showed LARP4 expression is set by codon-tRNA matching, identifying a translation-dependent coding-region instability determinant.","evidence":"Synonymous codon substitution panel and limiting-tRNA overexpression with mRNA level measurement","pmids":["28895529"],"confidence":"Medium","gaps":["Mechanistic link to ribosome elongation/co-translational decay not detailed","In vivo relevance of the CRD untested"]},{"year":2016,"claim":"Connected LARP4's biochemistry to a cellular phenotype, identifying it as an inhibitor of cancer cell migration and invasion.","evidence":"RNAi depletion, overexpression, transwell and 3D Matrigel invasion assays, and Co-IP of PABP with a cancer truncation mutant","pmids":["27615744"],"confidence":"Medium","gaps":["Molecular mechanism linking RNA activity to migration not yet defined here","Single-lab phenotype"]},{"year":2020,"claim":"Extended the deadenylation-protection model transcriptome-wide and pinpointed short poly(A) tails as the site of greatest LARP4 impact.","evidence":"Single-molecule PAT-seq in LARP4 knockout cells with time-course decay analysis","pmids":["32744499"],"confidence":"High","gaps":["Does not identify which specific deadenylase is opposed","Selectivity for particular mRNA classes not resolved"]},{"year":2020,"claim":"Demonstrated a physiological role for LARP4-mediated mRNA stabilization in T cell activation.","evidence":"BruChase-Seq nascent mRNA stability profiling and cytokine secretion assays in Larp4 knockout mice","pmids":["32735645"],"confidence":"Medium","gaps":["Direct binding of LARP4 to Nfkb1 mRNA not shown","Single lab"]},{"year":2021,"claim":"Consolidated the PAM2-MLLE interaction framework, formalizing how LARP4 docks onto PABP to stabilize it on poly(A) tails.","evidence":"Mechanistic review synthesizing prior biochemical PAM2-MLLE binding data","pmids":["33522422"],"confidence":"Medium","gaps":["Review consolidating prior work rather than new experiments","Functional distinction from LARP1 not resolved"]},{"year":2023,"claim":"Identified a distinct cytoskeletal function, showing LARP4 binds the force-exposed R21 domain of Filamin A to regulate migration.","evidence":"Reciprocal in vivo/in vitro Co-IP, FRAP, proximity ligation, F277A mutagenesis, and migration rescue assays","pmids":["37169020"],"confidence":"Medium","gaps":["Structural basis of the interaction not yet resolved here","Relationship between RNA-binding and FLNA-binding functions unclear"]},{"year":2024,"claim":"Resolved how LARP4 selectively promotes translation, mapping a CR2-RACK1 interaction that is separable from PABP binding.","evidence":"Yeast two-hybrid mapping, in vitro binding, AlphaFold2-Multimer, CR2 mutagenesis, polysome profiling, and luciferase reporters","pmids":["39898547"],"confidence":"High","gaps":["How RACK1 recruitment selects ARE-mRNAs mechanistically not fully defined","Structural validation of CR2-RACK1 contact beyond prediction limited"]},{"year":2024,"claim":"Linked LARP4 to mitochondrial biogenesis by showing it binds and supports expression of nuclear-encoded mitochondrial mRNAs.","evidence":"CLIP-seq target identification, quantitative proteomics after depletion, mitochondrial function assays, and re-expression rescue","pmids":["38164626"],"confidence":"Medium","gaps":["Whether the effect is via tail protection or CR2-RACK1 translation not dissected","Single lab"]},{"year":2024,"claim":"Showed LARP4 is hijacked by PEDV coronavirus, with cytoplasmic LARP4 and PABPC1 enhancing viral mRNA translation.","evidence":"Subcellular fractionation, knockdown, reporter assays, and rabbit reticulocyte lysate in vitro translation with purified proteins","pmids":["39182469"],"confidence":"Medium","gaps":["Mechanism of CRM1-independent shuttling not defined","Generality across other viruses untested"]},{"year":2024,"claim":"Identified cooperation with the cytoplasmic poly(A) polymerase TENT5C in protecting globin mRNA tails during erythropoiesis.","evidence":"Co-AP/MS proteomics, poly(A) tail sequencing, LARP4/5 depletion, and TENT5C catalytic mutant mice (preprint)","pmids":["bio_10.1101_2024.11.14.623596"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Stoichiometry and timing of the transient TENT5C association undefined"]},{"year":2025,"claim":"Determined the atomic structure of the LARP4-FLNA R21 complex and showed LARP4 competes with integrin tails for the same site.","evidence":"X-ray crystallography of FLNA R21 with LARP4 peptide, mutagenesis, in vitro competition, and migration assays","pmids":["40466905"],"confidence":"High","gaps":["Functional consequence of integrin competition in vivo not established","How N275S alters membrane localization independent of FLNA unexplained"]},{"year":2025,"claim":"Established LARP4 as a driver of T cell exhaustion through OXPHOS mRNA hypertranslation, defining a targetable node for anti-tumor immunity.","evidence":"Conditional Larp4 knockout in T cells, translatome profiling, mitochondrial assays, in vivo tumor models, and CAR-T functional assays","pmids":["40696044"],"confidence":"High","gaps":["Upstream signals controlling LARP4 activity in exhausted T cells not defined","Whether CR2-RACK1 or tail-protection mediates OXPHOS selectivity not dissected"]},{"year":2025,"claim":"Showed LARP4 controls naive T cell quiescence exit and differentiation, and demonstrated therapeutic inhibition with a peptide.","evidence":"Conditional knockout mouse, mRNA stability analysis, differentiation assays, and a peptide inhibitor (LIPEP) in autoimmune/allergy models","pmids":["41102557"],"confidence":"High","gaps":["Molecular target/mechanism of the LIPEP peptide not detailed","Specific quiescence-controlling mRNAs not fully enumerated"]},{"year":null,"claim":"How LARP4's separable activities — poly(A)/PABP tail protection, CR2-RACK1 translational enhancement, and FLNA-mediated cytoskeletal regulation — are coordinated and selectively deployed across mRNA classes and cell contexts remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model integrating RNA and cytoskeletal functions","Identity of the specific deadenylase(s) opposed not established","Determinants of mRNA-subset selectivity (ARE, OXPHOS, mitochondrial) not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,5,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[8,11,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,12,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,12]}],"complexes":[],"partners":["PABPC1","RACK1","FLNA","TENT5C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q71RC2","full_name":"La-related protein 4","aliases":["La ribonucleoprotein domain family member 4"],"length_aa":724,"mass_kda":80.6,"function":"RNA binding protein that binds to the poly-A tract of mRNA molecules (PubMed:21098120). Associates with the 40S ribosomal subunit and with polysomes (PubMed:21098120). Plays a role in the regulation of mRNA translation (PubMed:21098120). Plays a role in the regulation of cell morphology and cytoskeletal organization (PubMed:21834987, PubMed:27615744)","subcellular_location":"Cytoplasm, Stress granule; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q71RC2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LARP4","classification":"Not Classified","n_dependent_lines":218,"n_total_lines":1208,"dependency_fraction":0.1804635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BPNT1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP19","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LARP4","total_profiled":1310},"omim":[{"mim_id":"618657","title":"La RIBONUCLEOPROTEIN 4; LARP4","url":"https://www.omim.org/entry/618657"},{"mim_id":"616513","title":"La RIBONUCLEOPROTEIN 4B; LARP4B","url":"https://www.omim.org/entry/616513"},{"mim_id":"612026","title":"La RIBONUCLEOPROTEIN 7, TRANSCRIPTIONAL REGULATOR; LARP7","url":"https://www.omim.org/entry/612026"},{"mim_id":"611300","title":"La RIBONUCLEOPROTEIN 6, TRANSLATIONAL REGULATOR; LARP6","url":"https://www.omim.org/entry/611300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LARP4"},"hgnc":{"alias_symbol":["PP13296"],"prev_symbol":[]},"alphafold":{"accession":"Q71RC2","domains":[{"cath_id":"1.10.10.10","chopping":"116-196","consensus_level":"medium","plddt":92.8484,"start":116,"end":196},{"cath_id":"3.30.70.330","chopping":"198-279","consensus_level":"medium","plddt":90.6395,"start":198,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q71RC2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q71RC2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q71RC2-F1-predicted_aligned_error_v6.png","plddt_mean":54.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LARP4","jax_strain_url":"https://www.jax.org/strain/search?query=LARP4"},"sequence":{"accession":"Q71RC2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q71RC2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q71RC2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q71RC2"}},"corpus_meta":[{"pmid":"28893265","id":"PMC_28893265","title":"Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28893265","citation_count":448,"is_preprint":false},{"pmid":"28895529","id":"PMC_28895529","title":"LARP4 mRNA codon-tRNA match contributes to LARP4 activity for ribosomal protein mRNA poly(A) tail length protection.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28895529","citation_count":44,"is_preprint":false},{"pmid":"31911757","id":"PMC_31911757","title":"Up-regulation of circ_LARP4 suppresses cell proliferation and migration in ovarian cancer by regulating miR-513b-5p/LARP4 axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31911757","citation_count":43,"is_preprint":false},{"pmid":"31642110","id":"PMC_31642110","title":"Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA-424 in osteosarcoma.","date":"2019","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/31642110","citation_count":41,"is_preprint":false},{"pmid":"27615744","id":"PMC_27615744","title":"The RNA-binding protein LARP4 regulates cancer cell migration and invasion.","date":"2016","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27615744","citation_count":36,"is_preprint":false},{"pmid":"33522422","id":"PMC_33522422","title":"LARP1 and LARP4: up close with PABP for mRNA 3' poly(A) protection and stabilization.","date":"2021","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/33522422","citation_count":33,"is_preprint":false},{"pmid":"31897898","id":"PMC_31897898","title":"Circular RNA_LARP4 Sponges miR-1323 and Hampers Progression of Esophageal Squamous Cell Carcinoma Through Modulating PTEN/PI3K/AKT Pathway.","date":"2020","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31897898","citation_count":33,"is_preprint":false},{"pmid":"32744499","id":"PMC_32744499","title":"Single molecule poly(A) tail-seq shows LARP4 opposes deadenylation throughout mRNA lifespan with most impact on short tails.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32744499","citation_count":31,"is_preprint":false},{"pmid":"32891769","id":"PMC_32891769","title":"Circ_LARP4 regulates high glucose-induced cell proliferation, apoptosis, and fibrosis in mouse mesangial cells.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32891769","citation_count":19,"is_preprint":false},{"pmid":"32495863","id":"PMC_32495863","title":"Circular RNA_LARP4 inhibits cell migration and invasion of prostate cancer by targeting FOXO3A.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32495863","citation_count":17,"is_preprint":false},{"pmid":"32735645","id":"PMC_32735645","title":"Transcriptome-wide stability analysis uncovers LARP4-mediated NFκB1 mRNA stabilization during T cell activation.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32735645","citation_count":14,"is_preprint":false},{"pmid":"38164626","id":"PMC_38164626","title":"LARP4 is an RNA-binding protein that binds nuclear-encoded mitochondrial mRNAs to promote mitochondrial function.","date":"2024","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38164626","citation_count":13,"is_preprint":false},{"pmid":"26644407","id":"PMC_26644407","title":"LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26644407","citation_count":12,"is_preprint":false},{"pmid":"37479138","id":"PMC_37479138","title":"Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland.","date":"2023","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37479138","citation_count":11,"is_preprint":false},{"pmid":"39898547","id":"PMC_39898547","title":"The short conserved region-2 of LARP4 interacts with ribosome-associated RACK1 and promotes translation.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39898547","citation_count":10,"is_preprint":false},{"pmid":"32141555","id":"PMC_32141555","title":"Circular RNA_LARP4 inhibits the progression of non-small-cell lung cancer by regulating the expression of SMAD7.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32141555","citation_count":10,"is_preprint":false},{"pmid":"40696044","id":"PMC_40696044","title":"LARP4-mediated hypertranslation drives T cell dysfunction in tumors.","date":"2025","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40696044","citation_count":8,"is_preprint":false},{"pmid":"31799660","id":"PMC_31799660","title":"Circular RNA_LARP4 inhibits cell proliferation and invasion of nasopharyngeal carcinoma by repressing ROCK1.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31799660","citation_count":8,"is_preprint":false},{"pmid":"37169020","id":"PMC_37169020","title":"Interaction of LARP4 to filamin A mechanosensing domain regulates cell migrations.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37169020","citation_count":8,"is_preprint":false},{"pmid":"36730544","id":"PMC_36730544","title":"CircBNC2 affects epithelial ovarian cancer progression through the miR-223-3p/ LARP4 axis.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/36730544","citation_count":7,"is_preprint":false},{"pmid":"39182469","id":"PMC_39182469","title":"Cellular RNA-binding proteins LARP4 and PABPC1 synergistically facilitate viral translation of coronavirus PEDV.","date":"2024","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39182469","citation_count":4,"is_preprint":false},{"pmid":"33378005","id":"PMC_33378005","title":"Circular RNA_LARP4 inhibits cell proliferation and invasion of nasopharyngeal carcinoma by repressing ROCK1.","date":"2020","source":"European review for medical and pharmacological 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40466905","citation_count":0,"is_preprint":false},{"pmid":"39554137","id":"PMC_39554137","title":"The short conserved region-2 of LARP4 interacts with ribosome-associated RACK1 and promotes translation.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39554137","citation_count":0,"is_preprint":false},{"pmid":"35365990","id":"PMC_35365990","title":"[Overexpression of circ_LARP4 inhibits the proliferation and migration of MCF-7 human breast cancer cells and its mechanism].","date":"2022","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35365990","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.14.623596","title":"Efficient globin production during terminal erythropoiesis depends on the synergistic action of TENT5C poly(A) polymerase and LARP4/5","date":"2024-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.14.623596","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16078,"output_tokens":4571,"usd":0.0584,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12638,"output_tokens":4479,"usd":0.087582,"stage2_stop_reason":"end_turn"},"total_usd":0.145982,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"LARP4 binds poly(A) RNA and poly(A)-binding protein (PABP), and its PABP-interaction domain and RNA-binding module are required for net lengthening of poly(A) tails (PATs) of heterologous mRNAs including ribosomal protein (RP) mRNAs, with concomitant mRNA stabilization. Genetic deletion of LARP4 decreases PAT length and RP mRNA stability. The RNA-binding module is sensitive to poly(A) 3'-termini, consistent with protection from deadenylation.\",\n      \"method\": \"Genetic knockout, overexpression, PAT-seq, domain mutagenesis, in-cell assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, OE, domain mutagenesis, PAT-seq) in a single rigorous study with clear mechanistic readouts\",\n      \"pmids\": [\"28895529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LARP4 mRNA 3'UTR contains a conserved AU-rich element (ARE) that destabilizes mRNA. Tristetraprolin (TTP) binds LARP4 mRNA in vivo and decreases cellular LARP4 levels; TTP knockout cells accumulate higher LARP4. TNF-α stimulation induces a TTP pulse that causes a transient decrease in LARP4 mRNA and protein, establishing LARP4 as a target of TNF-α–TTP post-transcriptional regulation.\",\n      \"method\": \"β-globin reporter stability assay, RNA co-immunoprecipitation, TTP gene knockout mouse cells, TNF-α stimulation\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, KO cells, reporter assay, and cytokine stimulation time-course, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26644407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Single-molecule PAT-seq (SM-PAT-seq) transcriptome-wide analysis in LARP4 knockout versus control cells shows LARP4 opposes deadenylation throughout mRNA lifespan, with greatest impact at short poly(A) tails of 30–75 nucleotides. Accelerated deadenylation in KO cells at PATs <75 nt is consistent with greater PABP dissociation in the absence of LARP4.\",\n      \"method\": \"SM-PAT-seq (single-molecule nucleotide-resolution transcriptome-wide poly(A) tail sequencing), LARP4 knockout cells, time-course PAT decay analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide single-molecule method in KO cells with time-course analysis, replicating and extending prior mechanistic findings\",\n      \"pmids\": [\"32744499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LARP4 depletion in PC3 and MDA-MB-231 cancer cells increases cell migration, invasion, and invasive protrusions in 3D Matrigel. Overexpression reduces cell elongation. A cancer-associated truncation mutant shows enhanced interaction with PABP and enhanced effects on cell morphology, establishing LARP4 as an inhibitor of cancer cell migration and invasion.\",\n      \"method\": \"RNAi depletion, overexpression, transwell migration/invasion assay, 3D Matrigel, Co-immunoprecipitation of PABP with truncation mutant\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — clean KD/OE with defined cellular phenotype and partial mechanistic follow-up (PABP interaction), single lab\",\n      \"pmids\": [\"27615744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LARP4 knockout in mice destabilizes Nfκb1 mRNAs in CD4+ T cells and reduces secretion of IL-2 and IFN-γ upon T cell activation, placing LARP4 as a regulator of T cell activation-dependent mRNA stabilization.\",\n      \"method\": \"BruChase-Seq (transcriptome-wide nascent mRNA stability), Larp4 knockout mouse, cytokine secretion assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with transcriptome-wide stability assay and functional cytokine readout, single lab\",\n      \"pmids\": [\"32735645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LARP4 directly binds poly(A) and PABP (PABPC1), contains a PAM2 motif that interacts with the MLLE domain of PABP, and opposes deadenylation by stabilizing PABP on mRNA poly(A) tails. LARP1 and LARP4 are described as sharing these activities to protect mRNA 3' poly(A) tails from deadenylases.\",\n      \"method\": \"Review/mechanistic synthesis of prior biochemical data; PAM2-MLLE interaction established by prior in vitro binding assays referenced therein\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic summary with supporting biochemical framework, but primarily a review consolidating prior experimental evidence\",\n      \"pmids\": [\"33522422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARP4 interacts with the mechanosensing immunoglobulin-like repeat 21 (R21) domain of Filamin A (FLNA) through a force-exposed cryptic binding site. The LARP4 region responsible maps to residues around position 277 (F277 in human). A F277A mutation disrupts FLNA binding. FRAP of GFP-LARP4 shows mutant LARP4 diffuses faster than WT. LARP4 knockdown increases cell migration speed, and expression of FLNA-binding-deficient LARP4 fails to rescue, establishing that LARP4–FLNA interaction regulates cell migration.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), FRAP, proximity ligation assay, site-directed mutagenesis, LARP4 knockdown, cell migration assay\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vivo/in vitro binding, mutagenesis, FRAP, and functional migration rescue assay, single lab\",\n      \"pmids\": [\"37169020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The crystal structure of FLNA R21 in complex with the LARP4 peptide (residues Ala269–Asn281) was determined by X-ray crystallography, showing LARP4 forms an extended β strand that binds the cleft formed by β strands C and D of FLNA R21. The LARP4-binding site overlaps with the integrin β tail-binding region, and in vitro assays show LARP4 competes with integrin β7 tails for FLNA R21 binding. Cancer-associated A279Cfs*2 and experimental F277A mutations disrupt binding; N275S alters membrane localization without affecting FLNA binding.\",\n      \"method\": \"X-ray crystallography, protein-protein interaction assays, site-directed mutagenesis, cell migration assay, in vitro competition assay\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with mutagenesis and functional cell migration validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40466905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LARP4's conserved region-2 (CR2; positions 615–625) directly binds RACK1 (a ribosome-associated protein) at RACK1 propellers 5 and 6 (residues 200–317), as established by yeast two-hybrid mapping, in vitro binding, AlphaFold2-Multimer prediction, and confirmed by CR2 mutations that abolish RACK1 and ribosome association. CR2 mutations reduce LARP4's ability to stabilize ARE-containing mRNAs and impair LARP4-mediated translational efficiency of ARE-mRNAs, while PABP association is less affected, indicating independent interactions.\",\n      \"method\": \"Yeast two-hybrid domain mapping, in vitro binding assay, AlphaFold2-Multimer structural prediction, site-directed mutagenesis, polysome profiling, luciferase reporter assay, Co-immunoprecipitation\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vitro reconstitution, structural prediction, mutagenesis, and functional translation assays in one rigorous study\",\n      \"pmids\": [\"39898547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LARP4 preprint (same study as PMID 39898547): CR2 of LARP4 (positions 615–625) directly binds RACK1 region 200–317; CR2 mutations abolish RACK1/ribosome association without equally affecting PABP; LARP4 promotes translational efficiency of ARE-containing mRNAs via this CR2–RACK1 interaction.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, mutagenesis, polysome profiling, nanoLuc reporter assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — preprint version of peer-reviewed PMID 39898547; included only as it predates publication but is now superseded by the peer-reviewed paper\",\n      \"pmids\": [\"39554137\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LARP4 binds nuclear-encoded mitochondrial mRNAs (NEMmRNAs), particularly those encoding respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs). LARP4 depletion significantly reduces RCCP and MRP protein levels by quantitative proteomics and reduces mitochondrial function; LARP4 re-expression rescues mitochondrial respiratory function.\",\n      \"method\": \"CLIP-seq (systematic RBP-RNA target analysis across 150 RBPs), quantitative proteomics after LARP4 depletion, mitochondrial function assays, rescue by LARP4 re-expression\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — eCLIP/CLIP-based target identification plus quantitative proteomics and functional rescue, single lab\",\n      \"pmids\": [\"38164626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PEDV coronavirus infection induces nuclear-to-cytoplasmic shuttling of LARP4 via a CRM1-independent pathway. Cytoplasmic LARP4 binds the 3'UTR of PEDV mRNA with assistance from PABPC1 to facilitate viral mRNA translation. LARP4 knockdown reduces PABPC1-induced 3'UTR translation activity. Purified prokaryotic LARP4 and PABPC1 together enhance PEDV mRNA translation in a rabbit reticulocyte lysate (RRL) system.\",\n      \"method\": \"Subcellular fractionation/localization, LARP4 knockdown, RRL in vitro translation assay, reporter assays\",\n      \"journal\": \"Veterinary Microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro translation reconstitution in RRL plus cell-based localization and KD experiments, single lab\",\n      \"pmids\": [\"39182469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARP4 drives hypertranslation in exhausted/dysfunctional intratumoral T cells by selectively enhancing translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion, and enhances anti-tumor effector persistence. LARP4 knockdown in CAR-T cells prevents terminal exhaustion.\",\n      \"method\": \"Conditional Larp4 knockout in T cells, translatome profiling, mitochondrial function assays, in vivo tumor models, CAR-T cell functional assays\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with translatome profiling, mitochondrial functional readouts, and in vivo anti-tumor efficacy, multiple orthogonal approaches\",\n      \"pmids\": [\"40696044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of LARP4 in naive CD4+ T cells enhances quiescence and dampens quiescence exit by altering stability of mRNAs important for T cell activation, impairing differentiation into helper T cell subsets. A peptide inhibitor of LARP4 (LIPEP) mimics LARP4 deficiency and ameliorates autoimmune and allergic responses in mouse models.\",\n      \"method\": \"Conditional knockout mouse, mRNA stability analysis, T cell differentiation assays, peptide inhibitor in vivo mouse disease models\",\n      \"journal\": \"Nature Biomedical Engineering\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with mRNA stability assays and in vivo disease rescue, multiple orthogonal methods\",\n      \"pmids\": [\"41102557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LARP4 cooperates with TENT5C cytoplasmic poly(A) polymerase in erythropoiesis: LARP4/5 depletion leads to downregulation and poly(A) tail shortening of globin mRNAs. Proteomic experiments revealed a transient but specific association of TENT5C with LARP4/5. Lack of TENT5C catalytic activity is accompanied by compensatory upregulation of LARP4/5, indicating functional redundancy in protecting globin mRNA poly(A) tails.\",\n      \"method\": \"Proteomics (Co-AP/MS), poly(A) tail length sequencing, LARP4/5 depletion, TENT5C catalytic mutant knock-in mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with proteomic co-association, KO/depletion phenotype, and PAT-seq in a relevant primary cell context, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.11.14.623596\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The LARP4 mRNA contains a translation-dependent coding region determinant (CRD) of instability comprising <10% of codons; synonymous substitutions accommodating tRNA dynamics cause >20-fold variation in LARP4 mRNA levels. Overexpression of the most limiting tRNA increases LARP4 protein levels, indicating LARP4 expression is controlled by codon-tRNA matching during translation.\",\n      \"method\": \"Synonymous codon substitution, tRNA overexpression, mRNA level measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic synonymous codon substitution panel with tRNA manipulation, single lab, multiple genetic perturbations\",\n      \"pmids\": [\"28895529\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LARP4 is a cytoplasmic RNA-binding protein that binds poly(A) RNA and poly(A)-binding protein (PABP) via a PAM2-MLLE interaction, protecting mRNA poly(A) tails from deadenylation throughout mRNA lifespan; it also interacts with ribosome-associated RACK1 through its conserved region-2 (CR2) to promote translational efficiency of specific mRNA subsets (including ARE-containing and OXPHOS mRNAs), interacts with Filamin A's mechanosensing R21 domain to regulate cell migration, is post-transcriptionally downregulated by the TTP–TNF-α axis, and plays key roles in T cell activation, quiescence, and exhaustion by modulating mRNA stability and translation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LARP4 is a cytoplasmic RNA-binding protein that protects mRNA poly(A) tails from deadenylation and tunes the stability and translation of specific mRNA subsets [#0, #2]. It binds poly(A) RNA and poly(A)-binding protein (PABPC1) — engaging the PABP MLLE domain through its PAM2 motif — and its RNA-binding module, sensitive to poly(A) 3' termini, stabilizes PABP on tails to oppose deadenylation throughout mRNA lifespan, with the greatest effect on short tails of 30–75 nucleotides [#0, #2, #5]. A second, PABP-independent activity is mediated by its conserved region-2 (CR2), which directly binds the ribosome-associated protein RACK1 at propellers 5–6; this interaction is required for LARP4 to stabilize and promote the translational efficiency of ARE-containing mRNAs [#8]. Through these activities LARP4 supports translation of nuclear-encoded mitochondrial and oxidative phosphorylation mRNAs and respiratory chain function [#10, #12]. LARP4 also acts at the cytoskeleton, binding the force-exposed cryptic site in the mechanosensing R21 domain of Filamin A via a region around residue F277 — an interaction resolved at atomic resolution that overlaps the integrin β-tail site — and this LARP4–FLNA interaction restrains cell migration and invasion [#3, #6, #7]. LARP4 abundance is itself controlled post-transcriptionally: an AU-rich element in its 3'UTR makes it a target of the TNF-α–tristetraprolin axis [#1], and a translation-dependent codon-tRNA matching determinant in its coding region sets its expression level [#15]. In T cells, LARP4 governs activation-dependent mRNA stabilization, quiescence exit, and exhaustion, with its loss restoring mitochondrial fitness and anti-tumor effector persistence [#4, #12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established how LARP4 levels are themselves regulated, showing the RNA-stability machinery feeds back onto the regulator.\",\n      \"evidence\": \"β-globin reporter stability assay, RNA co-IP, TTP knockout cells, and TNF-α stimulation time-course\",\n      \"pmids\": [\"26644407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address LARP4's own molecular function on target mRNAs\", \"Physiological consequence of the transient TNF-α-induced LARP4 dip not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined LARP4's core biochemical activity: binding poly(A) and PABP to lengthen and stabilize mRNA poly(A) tails, answering what LARP4 does to mRNA.\",\n      \"evidence\": \"Genetic knockout, overexpression, PAT-seq, and domain mutagenesis with in-cell assays\",\n      \"pmids\": [\"28895529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptome-wide kinetics and tail-length dependence not yet resolved\", \"Translation-level consequences not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed LARP4 expression is set by codon-tRNA matching, identifying a translation-dependent coding-region instability determinant.\",\n      \"evidence\": \"Synonymous codon substitution panel and limiting-tRNA overexpression with mRNA level measurement\",\n      \"pmids\": [\"28895529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link to ribosome elongation/co-translational decay not detailed\", \"In vivo relevance of the CRD untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected LARP4's biochemistry to a cellular phenotype, identifying it as an inhibitor of cancer cell migration and invasion.\",\n      \"evidence\": \"RNAi depletion, overexpression, transwell and 3D Matrigel invasion assays, and Co-IP of PABP with a cancer truncation mutant\",\n      \"pmids\": [\"27615744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking RNA activity to migration not yet defined here\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the deadenylation-protection model transcriptome-wide and pinpointed short poly(A) tails as the site of greatest LARP4 impact.\",\n      \"evidence\": \"Single-molecule PAT-seq in LARP4 knockout cells with time-course decay analysis\",\n      \"pmids\": [\"32744499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify which specific deadenylase is opposed\", \"Selectivity for particular mRNA classes not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a physiological role for LARP4-mediated mRNA stabilization in T cell activation.\",\n      \"evidence\": \"BruChase-Seq nascent mRNA stability profiling and cytokine secretion assays in Larp4 knockout mice\",\n      \"pmids\": [\"32735645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of LARP4 to Nfkb1 mRNA not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the PAM2-MLLE interaction framework, formalizing how LARP4 docks onto PABP to stabilize it on poly(A) tails.\",\n      \"evidence\": \"Mechanistic review synthesizing prior biochemical PAM2-MLLE binding data\",\n      \"pmids\": [\"33522422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review consolidating prior work rather than new experiments\", \"Functional distinction from LARP1 not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a distinct cytoskeletal function, showing LARP4 binds the force-exposed R21 domain of Filamin A to regulate migration.\",\n      \"evidence\": \"Reciprocal in vivo/in vitro Co-IP, FRAP, proximity ligation, F277A mutagenesis, and migration rescue assays\",\n      \"pmids\": [\"37169020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the interaction not yet resolved here\", \"Relationship between RNA-binding and FLNA-binding functions unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how LARP4 selectively promotes translation, mapping a CR2-RACK1 interaction that is separable from PABP binding.\",\n      \"evidence\": \"Yeast two-hybrid mapping, in vitro binding, AlphaFold2-Multimer, CR2 mutagenesis, polysome profiling, and luciferase reporters\",\n      \"pmids\": [\"39898547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RACK1 recruitment selects ARE-mRNAs mechanistically not fully defined\", \"Structural validation of CR2-RACK1 contact beyond prediction limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked LARP4 to mitochondrial biogenesis by showing it binds and supports expression of nuclear-encoded mitochondrial mRNAs.\",\n      \"evidence\": \"CLIP-seq target identification, quantitative proteomics after depletion, mitochondrial function assays, and re-expression rescue\",\n      \"pmids\": [\"38164626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is via tail protection or CR2-RACK1 translation not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed LARP4 is hijacked by PEDV coronavirus, with cytoplasmic LARP4 and PABPC1 enhancing viral mRNA translation.\",\n      \"evidence\": \"Subcellular fractionation, knockdown, reporter assays, and rabbit reticulocyte lysate in vitro translation with purified proteins\",\n      \"pmids\": [\"39182469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CRM1-independent shuttling not defined\", \"Generality across other viruses untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified cooperation with the cytoplasmic poly(A) polymerase TENT5C in protecting globin mRNA tails during erythropoiesis.\",\n      \"evidence\": \"Co-AP/MS proteomics, poly(A) tail sequencing, LARP4/5 depletion, and TENT5C catalytic mutant mice (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.11.14.623596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Stoichiometry and timing of the transient TENT5C association undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Determined the atomic structure of the LARP4-FLNA R21 complex and showed LARP4 competes with integrin tails for the same site.\",\n      \"evidence\": \"X-ray crystallography of FLNA R21 with LARP4 peptide, mutagenesis, in vitro competition, and migration assays\",\n      \"pmids\": [\"40466905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of integrin competition in vivo not established\", \"How N275S alters membrane localization independent of FLNA unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established LARP4 as a driver of T cell exhaustion through OXPHOS mRNA hypertranslation, defining a targetable node for anti-tumor immunity.\",\n      \"evidence\": \"Conditional Larp4 knockout in T cells, translatome profiling, mitochondrial assays, in vivo tumor models, and CAR-T functional assays\",\n      \"pmids\": [\"40696044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling LARP4 activity in exhausted T cells not defined\", \"Whether CR2-RACK1 or tail-protection mediates OXPHOS selectivity not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed LARP4 controls naive T cell quiescence exit and differentiation, and demonstrated therapeutic inhibition with a peptide.\",\n      \"evidence\": \"Conditional knockout mouse, mRNA stability analysis, differentiation assays, and a peptide inhibitor (LIPEP) in autoimmune/allergy models\",\n      \"pmids\": [\"41102557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target/mechanism of the LIPEP peptide not detailed\", \"Specific quiescence-controlling mRNAs not fully enumerated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LARP4's separable activities — poly(A)/PABP tail protection, CR2-RACK1 translational enhancement, and FLNA-mediated cytoskeletal regulation — are coordinated and selectively deployed across mRNA classes and cell contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model integrating RNA and cytoskeletal functions\", \"Identity of the specific deadenylase(s) opposed not established\", \"Determinants of mRNA-subset selectivity (ARE, OXPHOS, mitochondrial) not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 5, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 12, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PABPC1\", \"RACK1\", \"FLNA\", \"TENT5C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}