{"gene":"LARP6","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2009,"finding":"LARP6 binds the conserved 5' stem-loop (5'SL) in the 5'UTR of type I collagen mRNAs (COL1A1 and COL1A2) in a sequence-specific manner with Kd ~1.4 nM, using a bipartite RNA binding domain (La motif + RRM) that contacts two single-stranded regions of the stem-loop. In the cytoplasm, LARP6 does not associate with polysomes; overexpression blocks ribosomal loading on collagen mRNAs, while knockdown also decreases polysomal loading. LARP6 activity is required for focal synthesis of collagen polypeptides at discrete ER regions.","method":"Cloning and biochemical binding assays (Kd determination), siRNA knockdown, polysome fractionation, collagen-GFP reporter imaging","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (binding assay, KD, siRNA, polysome profiling, live imaging) in a single study; foundational paper with 91 citations","pmids":["19917293"],"is_preprint":false},{"year":2014,"finding":"LARP6 requires synergy between its La motif (LaM) and RRM1, as well as the interdomain linker, for sequence-specific recognition of the collagen 5'SL RNA. Crystal/NMR structures of the LaM and RRM1 of human LARP6 revealed considerable structural variation from the prototypic La protein and an unprecedented fold for the RRM1; mutagenesis guided by the structures confirmed that neither domain alone is sufficient.","method":"X-ray crystallography/NMR structure determination, mutagenesis, RNA binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — structure determination with mutagenesis validation, strong mechanistic insight","pmids":["25488812"],"is_preprint":false},{"year":2014,"finding":"Five specific nucleotides within the single-stranded regions of the collagen 5'SL are critical for high-affinity LARP6 binding (mutation of individual nucleotides abolishes binding). T133 in the La domain is critical for protein folding, and loop 3 in the RRM is critical for 5'SL binding. Loop 3 also mediates interaction of LARP6 with the protein translocation channel SEC61; a LARP6 mutant that binds 5'SL but cannot interact with SEC61 acts as a dominant negative suppressor of collagen synthesis, indicating LARP6 targets collagen mRNAs to SEC61 translocons for coordinated translation.","method":"Gel mobility shift assay, mutagenesis, co-immunoprecipitation, dominant-negative overexpression","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding with mutagenesis plus functional dominant-negative assay linking SEC61 interaction to collagen synthesis","pmids":["25692237"],"is_preprint":false},{"year":2014,"finding":"LARP6 associates with collagen mRNAs at the ER membrane independently of translation (collagen mRNAs remain ER-associated even when translation is inhibited). Knockdown of LARP6 or depolymerization of nonmuscle myosin filaments releases collagen mRNAs from the ER membrane and causes hypermodification, poor secretion, and cytosolic accumulation of collagen polypeptides, indicating LARP6 and nonmuscle myosin cooperate to partition collagen mRNAs to the ER membrane prior to signal peptide synthesis for coordinated translation initiation.","method":"Subcellular fractionation, siRNA knockdown, nonmuscle myosin depolymerization, pulse-chase secretion assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal experiments (fractionation, KD, drug treatment) with defined phenotypic readouts","pmids":["25271881"],"is_preprint":false},{"year":2013,"finding":"FKBP3 (FK506 binding protein 3, also called FKBP25) interacts with LARP6 and co-precipitates collagen mRNAs. FK506 (tacrolimus) weakens the FKBP3–LARP6 interaction and reduces pull-down of collagen mRNAs with FKBP3, leading to aberrant translation of collagen mRNAs and prevention of collagen synthesis and fibrosis in vivo.","method":"Co-immunoprecipitation, pull-down of RNA, in vivo fibrosis model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal co-IP with functional consequence shown in vivo, single lab","pmids":["23755290"],"is_preprint":false},{"year":2016,"finding":"LARP6 is phosphorylated at S451 by the PI3K/Akt pathway in lung fibroblasts, and this phosphorylation is a prerequisite for phosphorylation at other serines (hierarchical order). S451A dominant-negative mutant drastically reduces collagen secretion and induces hypermodification of collagen α2(I) polypeptides, establishing Akt-mediated phosphorylation of LARP6 as critical for regulating translation and folding of collagen polypeptides.","method":"Mass spectrometry phosphorylation mapping, PI3K/Akt pathway inhibitors, dominant-negative overexpression, pulse-chase secretion assay, mutagenesis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — MS-based site mapping, mutagenesis, kinase inhibitor, and dominant-negative with collagen secretion readout; multiple orthogonal methods","pmids":["26932461"],"is_preprint":false},{"year":2017,"finding":"mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A double mutant acts as a dominant negative in collagen biosynthesis, retards secretion, and causes excessive posttranslational modifications. mTORC1 phosphorylation of LARP6 promotes its interaction with the accessory protein STRAP (needed for coordinated translation of collagen mRNAs) and releases LARP6 from the ER membrane, enabling a new round of translation.","method":"mTORC1 inhibitor (rapamycin), raptor knockdown, dominant-negative overexpression, co-immunoprecipitation with STRAP, subcellular fractionation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — kinase pathway manipulation, mutagenesis, co-IP, and fractionation with defined mechanistic outcome","pmids":["28112218"],"is_preprint":false},{"year":2014,"finding":"IGF-1 increases LARP6 expression and the level of COL1A1 and COL1A2 mRNA bound to LARP6 via PI3K/Akt/p70S6k signaling. Mutation of the 5'SL of Col1a1 mRNA (which inhibits LARP6 binding) or sequestration of LARP6 with a decoy RNA abolishes IGF-1-stimulated collagen type I synthesis, confirming that LARP6 binding to collagen mRNAs is essential for IGF-1's effect on collagen production.","method":"RNA immunoprecipitation (RIP) + qPCR, 5'SL mutation, RNA decoy sequestration, PI3K/Akt pathway inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — RIP-qPCR, mutagenesis, decoy approach, and pathway inhibitors converge on mechanism; 83 citations","pmids":["24469459"],"is_preprint":false},{"year":2021,"finding":"The La domain of LARP6 alone is necessary and sufficient for sequence-specific recognition of the collagen 5'SL RNA. A three-amino-acid RNK motif in the flexible loop connecting the second α-helix to the β-sheet of the La domain is critical for binding; mutation of any of these three residues abolishes binding. The RRM increases stability of the La domain–5'SL complex but does not make extensive contacts with 5'SL. The RNK motif is absent from other LARPs that cannot bind 5'SL.","method":"Mutagenesis, UV-crosslinking mapping, RNA binding assays, domain-deletion analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with crosslinking to map binding interface, functional validation","pmids":["34896113"],"is_preprint":false},{"year":2021,"finding":"CRTH2 (a prostaglandin D2 receptor), trafficked to the ER membrane in fibroblasts in a caveolin-1-dependent manner, binds the collagen mRNA recognition motif of LARP6 and promotes degradation of collagen mRNA. CRTH2 deficiency increases collagen biosynthesis and exacerbates fibrosis in mice, which is rescued by LARP6 depletion, placing CRTH2 as an upstream negative regulator of LARP6 function.","method":"Co-immunoprecipitation, caveolin-1-dependent trafficking assay, CRTH2 and LARP6 knockdown/knockout mouse models, epistasis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (LARP6 depletion rescues CRTH2 KO phenotype), Co-IP, and in vivo mouse experiments","pmids":["34223653"],"is_preprint":false},{"year":2024,"finding":"In Xenopus multiciliated cells (MCCs), LARP6 co-localizes with DNAAF6 in biomolecular condensates (dynein axonemal particles) and the two proteins synergize to control ciliogenesis. LARP6 binds tubulin alpha 1c-like mRNA encoding α-tubulin, a major ciliary axoneme component; a DNAAF6 mutant that cannot bind LARP6 fails to restore α-tubulin protein expression at the apical side of MCCs, demonstrating that the LARP6–DNAAF6 interaction in condensates regulates α-tubulin production during ciliogenesis.","method":"Co-localization in Xenopus embryo MCCs, co-immunoprecipitation, RNA binding assay, DNAAF6 morphant rescue with wild-type vs. binding-deficient mutant","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue with binding-deficient mutant in Xenopus model; single lab but orthogonal methods","pmids":["38762183"],"is_preprint":false},{"year":2025,"finding":"An intrinsically disordered N-terminal IDR of LARP6 restricts conformational flexibility of the adjacent La-module and forms auxiliary contacts with RNA, thereby narrowing RNA-binding selectivity. Deletion of the N-terminal IDR broadens LARP6 RNA footprints (iCLIP). This IDR-mediated selectivity is required for LARP6-driven cancer cell viability and invasion, as shown by mutagenesis and cellular functional assays.","method":"Mass spectrometry-based RNA interaction mapping in living cells, iCLIP, mutagenesis, cancer cell invasion/viability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — in-cell MS RNA interaction mapping, iCLIP, mutagenesis, and functional assays; multiple orthogonal methods in a single study","pmids":["41714637"],"is_preprint":false},{"year":2026,"finding":"LARP6 is upregulated in activated hepatic stellate cells (HSCs) in MASH/MetALD by JUNB transcriptional activation. eCLIP-ribosome profiling integration shows LARP6 interacts with >300 mature mRNAs including structural elements in COL1A1, COL1A2, and COL3A1 to regulate their translation. IP-mass spectrometry identified LARP6 protein-protein interactions with mRNA translation components and the actin cytoskeleton.","method":"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, HSC-specific siRNA knockdown","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — multiple genome-wide orthogonal methods (eCLIP, ribosome profiling, IP-MS) with functional validation in disease-relevant human model","pmids":["41746718"],"is_preprint":false},{"year":2025,"finding":"Solution NMR structure of the La domain of human LARP6 in the RNA-bound state reveals a non-canonical binding interface integrating electrostatic and hydrophobic contacts with shape complementarity for 5'SL recognition. Chemical shift perturbation, solvent paramagnetic relaxation enhancement, intermolecular NOEs, and targeted mutagenesis identify this interface; the La domain alone discriminates 5'SL from homopolymeric or purely helical hairpin RNAs with low-nanomolar affinity, overturning the view that the RRM is required for recognition.","method":"Solution NMR structure determination, chemical shift perturbation, solvent PRE, intermolecular NOEs, mutagenesis, RNA binding assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structure with mutagenesis validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.22.652967"],"is_preprint":true},{"year":2023,"finding":"LARP6 binds ZNF267 mRNA and regulates its stability and translation in colorectal cancer cells. Reduced ZNF267 by LARP6 inhibits downstream SGMS2 expression, causing ceramide/sphingomyelin imbalance and enhanced autophagy, thereby suppressing CRC progression.","method":"RIP-seq, RIP-qPCR, stable overexpression/knockdown, mRNA stability assay, autophagy assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP-seq identifies binding, functional cascade validated by KD/OE with multiple readouts; single lab","pmids":["36691044"],"is_preprint":false},{"year":2025,"finding":"In MDA-MB-231 triple-negative breast cancer cells, LARP6 directly binds mRNAs (iRIP-seq identifies CGACGAG binding motif) and regulates alternative splicing of >1000 events, with regulated genes enriched in DNA repair and cell cycle pathways, promoting cancer cell proliferation and invasion.","method":"iRIP-seq, RNA-seq, RT-qPCR, RIP-qPCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — iRIP-seq identifies direct binding with motif; functional link to AS regulation shown; single lab","pmids":["40050364"],"is_preprint":false}],"current_model":"LARP6 is an RNA-binding protein that uses its La domain (specifically the RNK motif) and flanking RRM1—with the N-terminal IDR restricting binding selectivity—to sequence-specifically recognize a conserved 5' stem-loop in the 5'UTR of type I and III collagen mRNAs, thereby targeting these mRNAs to the ER membrane (via interactions with SEC61 translocon and nonmuscle myosin filaments), regulating their translation in a coordinated manner facilitated by accessory proteins STRAP and FKBP3; LARP6 activity is post-translationally tuned by hierarchical phosphorylation at S451 (Akt) and S348/S409 (mTORC1), and LARP6 additionally functions in ciliogenesis by binding α-tubulin mRNA within DNAAF6-containing biomolecular condensates in multiciliated cells, and more broadly regulates alternative splicing and translation of hundreds of mRNAs in cancer contexts."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that LARP6 is a sequence-specific collagen mRNA-binding protein resolved how type I collagen mRNAs are distinguished from bulk mRNAs for specialized translational regulation at the ER.","evidence":"Biochemical binding assays (Kd ~1.4 nM), siRNA knockdown, polysome fractionation, and collagen-GFP reporter imaging in human fibroblasts","pmids":["19917293"],"confidence":"High","gaps":["Structural basis of 5′SL recognition unknown","Mechanism coupling LARP6 binding to ER membrane targeting not addressed","Physiological relevance in vivo not tested"]},{"year":2013,"claim":"Identification of FKBP3 as a LARP6-interacting protein showed that accessory factors modulate collagen mRNA engagement, and that pharmacological disruption (FK506) of this interaction blocks fibrosis in vivo.","evidence":"Co-immunoprecipitation, RNA pull-down, and in vivo fibrosis model with FK506 treatment","pmids":["23755290"],"confidence":"Medium","gaps":["Direct vs. bridged interaction between FKBP3 and LARP6 not resolved","Single-lab observation without independent replication"]},{"year":2014,"claim":"Structural and mutagenesis studies defined the bipartite La–RRM1 architecture required for 5′SL recognition and simultaneously revealed that LARP6 bridges collagen mRNAs to SEC61 translocons and the ER membrane via nonmuscle myosin filaments, establishing the mechanism of mRNA-to-translocon targeting.","evidence":"X-ray/NMR structures of LaM and RRM1, mutagenesis, gel-shift assays, dominant-negative SEC61-interaction-deficient mutant, subcellular fractionation, and myosin depolymerization in fibroblasts","pmids":["25488812","25692237","25271881"],"confidence":"High","gaps":["No co-crystal structure of LARP6 bound to 5′SL RNA","Direct binding interface between LARP6 and SEC61 not mapped at residue level","Role of nonmuscle myosin remains correlative"]},{"year":2014,"claim":"Showing that IGF-1 stimulates collagen synthesis through PI3K/Akt-dependent increase in LARP6 expression and collagen mRNA loading placed LARP6 downstream of growth factor signaling.","evidence":"RIP-qPCR, 5′SL mutation and RNA decoy sequestration, PI3K/Akt pathway inhibitors in fibroblasts","pmids":["24469459"],"confidence":"High","gaps":["Transcriptional vs. post-transcriptional regulation of LARP6 levels by IGF-1 not fully dissected"]},{"year":2016,"claim":"Mapping Akt phosphorylation of LARP6 at S451 as a hierarchical prerequisite for subsequent phosphorylation events established that post-translational modification directly controls collagen folding and secretion quality.","evidence":"Mass spectrometry phosphosite mapping, PI3K/Akt inhibitors, S451A dominant-negative mutant, pulse-chase secretion assay in lung fibroblasts","pmids":["26932461"],"confidence":"High","gaps":["Identity of downstream kinases phosphorylating other serines (beyond mTORC1) not fully resolved","Phosphorylation-dependent structural changes in LARP6 not characterized"]},{"year":2017,"claim":"Demonstrating mTORC1-dependent phosphorylation at S348/S409 explained how LARP6 cycles between ER-bound collagen mRNA complexes and soluble forms, coupling nutrient sensing to collagen production.","evidence":"Rapamycin treatment, raptor knockdown, S348A/S409A dominant-negative mutant, co-IP with STRAP, subcellular fractionation","pmids":["28112218"],"confidence":"High","gaps":["Temporal order of Akt vs. mTORC1 phosphorylation in a single translation cycle not resolved","STRAP's molecular role in translation coordination unclear"]},{"year":2021,"claim":"Pinpointing the RNK motif in the La domain as necessary and sufficient for 5′SL recognition refined the binding model and explained why other LARP family members cannot bind collagen mRNAs.","evidence":"UV-crosslinking mapping, domain deletion, mutagenesis, and RNA binding assays","pmids":["34896113"],"confidence":"High","gaps":["Atomic-resolution structure of the RNK–5′SL interface not yet available from peer-reviewed work"]},{"year":2021,"claim":"Discovery that the prostaglandin D2 receptor CRTH2 binds LARP6's collagen mRNA recognition site and promotes collagen mRNA degradation identified an upstream negative regulator, with genetic epistasis confirming LARP6 as the downstream effector in fibrosis.","evidence":"Co-IP, CRTH2/LARP6 double depletion epistasis, caveolin-1-dependent trafficking, CRTH2 knockout mouse fibrosis model","pmids":["34223653"],"confidence":"High","gaps":["Mechanism by which CRTH2 binding to LARP6 triggers mRNA degradation unresolved","Whether CRTH2–LARP6 interaction occurs on all collagen mRNA targets not tested"]},{"year":2023,"claim":"Identification of ZNF267 mRNA as a non-collagen LARP6 target in colorectal cancer demonstrated LARP6 regulates mRNA stability and translation beyond collagens, linking it to ceramide/sphingomyelin balance and autophagy.","evidence":"RIP-seq, RIP-qPCR, stable knockdown/overexpression, mRNA stability and autophagy assays in CRC cells","pmids":["36691044"],"confidence":"Medium","gaps":["Whether LARP6 binds ZNF267 mRNA via a stem-loop analogous to collagen 5′SL is unknown","Single-lab finding not independently replicated"]},{"year":2024,"claim":"Showing that LARP6 localizes to DNAAF6-containing biomolecular condensates and binds α-tubulin mRNA in multiciliated cells extended LARP6 function to ciliogenesis, independent of collagen.","evidence":"Co-localization, co-IP, RNA binding assay, and DNAAF6 morphant rescue with binding-deficient mutant in Xenopus MCCs","pmids":["38762183"],"confidence":"Medium","gaps":["RNA element in α-tubulin mRNA recognized by LARP6 not mapped","Whether LARP6 functions in mammalian ciliogenesis not tested"]},{"year":2025,"claim":"Demonstrating that the N-terminal IDR restricts LARP6 RNA-binding selectivity and is required for cancer cell viability and invasion established a regulatory mechanism that explains how LARP6 discriminates among potential mRNA targets.","evidence":"In-cell MS RNA interaction mapping, iCLIP, IDR deletion mutagenesis, cancer cell invasion/viability assays","pmids":["41714637"],"confidence":"High","gaps":["Structural basis of IDR–La module interaction not resolved at atomic level","Whether IDR-mediated selectivity operates in normal (non-cancer) physiology not tested"]},{"year":2025,"claim":"iRIP-seq in breast cancer cells revealed LARP6 binds a CGACGAG motif on >1000 mRNAs and regulates alternative splicing, expanding its functional repertoire beyond translational control.","evidence":"iRIP-seq with motif discovery, RNA-seq, RT-qPCR in MDA-MB-231 cells","pmids":["40050364"],"confidence":"Medium","gaps":["Mechanism by which an RNA-binding protein regulates splicing not elucidated","Overlap between iRIP-seq and eCLIP targets from other studies not assessed"]},{"year":2026,"claim":"Genome-wide eCLIP and ribosome profiling in activated hepatic stellate cells showed LARP6 interacts with >300 mRNAs and controls their translation, confirming broad translational regulatory scope in a disease-relevant fibrotic context.","evidence":"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, HSC-specific siRNA knockdown","pmids":["41746718"],"confidence":"High","gaps":["Rules distinguishing translationally regulated from non-regulated LARP6-bound mRNAs unknown","Contribution of individual non-collagen targets to fibrosis phenotype not dissected"]},{"year":null,"claim":"A peer-reviewed atomic-resolution structure of the LARP6 La domain bound to 5′SL RNA and the mechanism by which LARP6 regulates alternative splicing remain to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No peer-reviewed co-structure of LARP6–5′SL complex","Splicing regulatory mechanism entirely uncharacterized","How LARP6 selectivity for collagen vs. non-collagen targets is determined genome-wide is unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,8,10,11,12,14,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,6,9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,5,6,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,15]}],"complexes":[],"partners":["SEC61A1","FKBP3","STRAP","DNAAF6","CRTH2","MYH9"],"other_free_text":[]},"mechanistic_narrative":"LARP6 is an RNA-binding protein that orchestrates collagen biosynthesis by sequence-specifically recognizing a conserved 5′ stem-loop (5′SL) in the 5′UTR of type I and type III collagen mRNAs and directing their coordinated translation at the ER membrane. High-affinity 5′SL recognition (~1.4 nM Kd) is conferred by an RNK motif within the La domain, with the adjacent RRM1 stabilizing the complex and an N-terminal intrinsically disordered region restricting RNA-binding selectivity; LARP6 targets collagen mRNAs to SEC61 translocons via its RRM loop 3 and cooperates with nonmuscle myosin filaments to partition these mRNAs at the ER independently of translation [PMID:19917293, PMID:25488812, PMID:34896113, PMID:25692237, PMID:25271881, PMID:41714637]. LARP6 activity is tuned by hierarchical phosphorylation—Akt at S451 and mTORC1 at S348/S409—which regulates interaction with the accessory protein STRAP, ER membrane cycling, and proper collagen folding and secretion [PMID:26932461, PMID:28112218]. Beyond collagen, LARP6 functions in ciliogenesis by binding α-tubulin mRNA within DNAAF6-containing biomolecular condensates in multiciliated cells, and genome-wide eCLIP/iCLIP studies reveal it interacts with hundreds of mRNAs, regulating translation and alternative splicing in contexts including hepatic stellate cell activation and cancer [PMID:38762183, PMID:41746718, PMID:40050364]."},"prefetch_data":{"uniprot":{"accession":"Q9BRS8","full_name":"La-related protein 6","aliases":["Acheron","Achn","La ribonucleoprotein domain family member 6"],"length_aa":491,"mass_kda":54.7,"function":"Regulates the coordinated translation of type I collagen alpha-1 and alpha-2 mRNAs, CO1A1 and CO1A2. Stabilizes mRNAs through high-affinity binding of a stem-loop structure in their 5' UTR. This regulation requires VIM and MYH10 filaments, and the helicase DHX9","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BRS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LARP6","classification":"Not Classified","n_dependent_lines":45,"n_total_lines":1208,"dependency_fraction":0.037251655629139076},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LARP6","total_profiled":1310},"omim":[{"mim_id":"618657","title":"La RIBONUCLEOPROTEIN 4; LARP4","url":"https://www.omim.org/entry/618657"},{"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"},{"mim_id":"609159","title":"NODAL MODULATOR 3; NOMO3","url":"https://www.omim.org/entry/609159"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":123.6}],"url":"https://www.proteinatlas.org/search/LARP6"},"hgnc":{"alias_symbol":["acheron","FLJ11196"],"prev_symbol":[]},"alphafold":{"accession":"Q9BRS8","domains":[{"cath_id":"1.10.10.10","chopping":"89-168","consensus_level":"high","plddt":90.4305,"start":89,"end":168},{"cath_id":"3.30.70.330","chopping":"184-289","consensus_level":"high","plddt":71.9516,"start":184,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRS8-F1-predicted_aligned_error_v6.png","plddt_mean":60.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LARP6","jax_strain_url":"https://www.jax.org/strain/search?query=LARP6"},"sequence":{"accession":"Q9BRS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRS8"}},"corpus_meta":[{"pmid":"19917293","id":"PMC_19917293","title":"Binding of LARP6 to the conserved 5' stem-loop regulates translation of mRNAs encoding type I collagen.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19917293","citation_count":91,"is_preprint":false},{"pmid":"24469459","id":"PMC_24469459","title":"Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24469459","citation_count":83,"is_preprint":false},{"pmid":"27011170","id":"PMC_27011170","title":"LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27011170","citation_count":77,"is_preprint":false},{"pmid":"25488812","id":"PMC_25488812","title":"Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25488812","citation_count":55,"is_preprint":false},{"pmid":"30674965","id":"PMC_30674965","title":"Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30674965","citation_count":38,"is_preprint":false},{"pmid":"25692237","id":"PMC_25692237","title":"Characterization of binding of LARP6 to the 5' stem-loop of collagen mRNAs: implications for synthesis of type I collagen.","date":"2014","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/25692237","citation_count":36,"is_preprint":false},{"pmid":"17383118","id":"PMC_17383118","title":"Acheron, a novel member of the Lupus Antigen family, is induced during the programmed cell death of skeletal muscles in the moth Manduca sexta.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17383118","citation_count":34,"is_preprint":false},{"pmid":"26932461","id":"PMC_26932461","title":"Akt mediated phosphorylation of LARP6; 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In the cytoplasm, LARP6 does not associate with polysomes; overexpression blocks ribosomal loading on collagen mRNAs, while knockdown also decreases polysomal loading. LARP6 activity is required for focal synthesis of collagen polypeptides at discrete ER regions.\",\n      \"method\": \"Cloning and biochemical binding assays (Kd determination), siRNA knockdown, polysome fractionation, collagen-GFP reporter imaging\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (binding assay, KD, siRNA, polysome profiling, live imaging) in a single study; foundational paper with 91 citations\",\n      \"pmids\": [\"19917293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LARP6 requires synergy between its La motif (LaM) and RRM1, as well as the interdomain linker, for sequence-specific recognition of the collagen 5'SL RNA. Crystal/NMR structures of the LaM and RRM1 of human LARP6 revealed considerable structural variation from the prototypic La protein and an unprecedented fold for the RRM1; mutagenesis guided by the structures confirmed that neither domain alone is sufficient.\",\n      \"method\": \"X-ray crystallography/NMR structure determination, mutagenesis, RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure determination with mutagenesis validation, strong mechanistic insight\",\n      \"pmids\": [\"25488812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Five specific nucleotides within the single-stranded regions of the collagen 5'SL are critical for high-affinity LARP6 binding (mutation of individual nucleotides abolishes binding). T133 in the La domain is critical for protein folding, and loop 3 in the RRM is critical for 5'SL binding. Loop 3 also mediates interaction of LARP6 with the protein translocation channel SEC61; a LARP6 mutant that binds 5'SL but cannot interact with SEC61 acts as a dominant negative suppressor of collagen synthesis, indicating LARP6 targets collagen mRNAs to SEC61 translocons for coordinated translation.\",\n      \"method\": \"Gel mobility shift assay, mutagenesis, co-immunoprecipitation, dominant-negative overexpression\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding with mutagenesis plus functional dominant-negative assay linking SEC61 interaction to collagen synthesis\",\n      \"pmids\": [\"25692237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LARP6 associates with collagen mRNAs at the ER membrane independently of translation (collagen mRNAs remain ER-associated even when translation is inhibited). Knockdown of LARP6 or depolymerization of nonmuscle myosin filaments releases collagen mRNAs from the ER membrane and causes hypermodification, poor secretion, and cytosolic accumulation of collagen polypeptides, indicating LARP6 and nonmuscle myosin cooperate to partition collagen mRNAs to the ER membrane prior to signal peptide synthesis for coordinated translation initiation.\",\n      \"method\": \"Subcellular fractionation, siRNA knockdown, nonmuscle myosin depolymerization, pulse-chase secretion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal experiments (fractionation, KD, drug treatment) with defined phenotypic readouts\",\n      \"pmids\": [\"25271881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FKBP3 (FK506 binding protein 3, also called FKBP25) interacts with LARP6 and co-precipitates collagen mRNAs. FK506 (tacrolimus) weakens the FKBP3–LARP6 interaction and reduces pull-down of collagen mRNAs with FKBP3, leading to aberrant translation of collagen mRNAs and prevention of collagen synthesis and fibrosis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, pull-down of RNA, in vivo fibrosis model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal co-IP with functional consequence shown in vivo, single lab\",\n      \"pmids\": [\"23755290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LARP6 is phosphorylated at S451 by the PI3K/Akt pathway in lung fibroblasts, and this phosphorylation is a prerequisite for phosphorylation at other serines (hierarchical order). S451A dominant-negative mutant drastically reduces collagen secretion and induces hypermodification of collagen α2(I) polypeptides, establishing Akt-mediated phosphorylation of LARP6 as critical for regulating translation and folding of collagen polypeptides.\",\n      \"method\": \"Mass spectrometry phosphorylation mapping, PI3K/Akt pathway inhibitors, dominant-negative overexpression, pulse-chase secretion assay, mutagenesis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — MS-based site mapping, mutagenesis, kinase inhibitor, and dominant-negative with collagen secretion readout; multiple orthogonal methods\",\n      \"pmids\": [\"26932461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A double mutant acts as a dominant negative in collagen biosynthesis, retards secretion, and causes excessive posttranslational modifications. mTORC1 phosphorylation of LARP6 promotes its interaction with the accessory protein STRAP (needed for coordinated translation of collagen mRNAs) and releases LARP6 from the ER membrane, enabling a new round of translation.\",\n      \"method\": \"mTORC1 inhibitor (rapamycin), raptor knockdown, dominant-negative overexpression, co-immunoprecipitation with STRAP, subcellular fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase pathway manipulation, mutagenesis, co-IP, and fractionation with defined mechanistic outcome\",\n      \"pmids\": [\"28112218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IGF-1 increases LARP6 expression and the level of COL1A1 and COL1A2 mRNA bound to LARP6 via PI3K/Akt/p70S6k signaling. Mutation of the 5'SL of Col1a1 mRNA (which inhibits LARP6 binding) or sequestration of LARP6 with a decoy RNA abolishes IGF-1-stimulated collagen type I synthesis, confirming that LARP6 binding to collagen mRNAs is essential for IGF-1's effect on collagen production.\",\n      \"method\": \"RNA immunoprecipitation (RIP) + qPCR, 5'SL mutation, RNA decoy sequestration, PI3K/Akt pathway inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP-qPCR, mutagenesis, decoy approach, and pathway inhibitors converge on mechanism; 83 citations\",\n      \"pmids\": [\"24469459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The La domain of LARP6 alone is necessary and sufficient for sequence-specific recognition of the collagen 5'SL RNA. A three-amino-acid RNK motif in the flexible loop connecting the second α-helix to the β-sheet of the La domain is critical for binding; mutation of any of these three residues abolishes binding. The RRM increases stability of the La domain–5'SL complex but does not make extensive contacts with 5'SL. The RNK motif is absent from other LARPs that cannot bind 5'SL.\",\n      \"method\": \"Mutagenesis, UV-crosslinking mapping, RNA binding assays, domain-deletion analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with crosslinking to map binding interface, functional validation\",\n      \"pmids\": [\"34896113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTH2 (a prostaglandin D2 receptor), trafficked to the ER membrane in fibroblasts in a caveolin-1-dependent manner, binds the collagen mRNA recognition motif of LARP6 and promotes degradation of collagen mRNA. CRTH2 deficiency increases collagen biosynthesis and exacerbates fibrosis in mice, which is rescued by LARP6 depletion, placing CRTH2 as an upstream negative regulator of LARP6 function.\",\n      \"method\": \"Co-immunoprecipitation, caveolin-1-dependent trafficking assay, CRTH2 and LARP6 knockdown/knockout mouse models, epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (LARP6 depletion rescues CRTH2 KO phenotype), Co-IP, and in vivo mouse experiments\",\n      \"pmids\": [\"34223653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Xenopus multiciliated cells (MCCs), LARP6 co-localizes with DNAAF6 in biomolecular condensates (dynein axonemal particles) and the two proteins synergize to control ciliogenesis. LARP6 binds tubulin alpha 1c-like mRNA encoding α-tubulin, a major ciliary axoneme component; a DNAAF6 mutant that cannot bind LARP6 fails to restore α-tubulin protein expression at the apical side of MCCs, demonstrating that the LARP6–DNAAF6 interaction in condensates regulates α-tubulin production during ciliogenesis.\",\n      \"method\": \"Co-localization in Xenopus embryo MCCs, co-immunoprecipitation, RNA binding assay, DNAAF6 morphant rescue with wild-type vs. binding-deficient mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue with binding-deficient mutant in Xenopus model; single lab but orthogonal methods\",\n      \"pmids\": [\"38762183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An intrinsically disordered N-terminal IDR of LARP6 restricts conformational flexibility of the adjacent La-module and forms auxiliary contacts with RNA, thereby narrowing RNA-binding selectivity. Deletion of the N-terminal IDR broadens LARP6 RNA footprints (iCLIP). This IDR-mediated selectivity is required for LARP6-driven cancer cell viability and invasion, as shown by mutagenesis and cellular functional assays.\",\n      \"method\": \"Mass spectrometry-based RNA interaction mapping in living cells, iCLIP, mutagenesis, cancer cell invasion/viability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in-cell MS RNA interaction mapping, iCLIP, mutagenesis, and functional assays; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"41714637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LARP6 is upregulated in activated hepatic stellate cells (HSCs) in MASH/MetALD by JUNB transcriptional activation. eCLIP-ribosome profiling integration shows LARP6 interacts with >300 mature mRNAs including structural elements in COL1A1, COL1A2, and COL3A1 to regulate their translation. IP-mass spectrometry identified LARP6 protein-protein interactions with mRNA translation components and the actin cytoskeleton.\",\n      \"method\": \"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, HSC-specific siRNA knockdown\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple genome-wide orthogonal methods (eCLIP, ribosome profiling, IP-MS) with functional validation in disease-relevant human model\",\n      \"pmids\": [\"41746718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Solution NMR structure of the La domain of human LARP6 in the RNA-bound state reveals a non-canonical binding interface integrating electrostatic and hydrophobic contacts with shape complementarity for 5'SL recognition. Chemical shift perturbation, solvent paramagnetic relaxation enhancement, intermolecular NOEs, and targeted mutagenesis identify this interface; the La domain alone discriminates 5'SL from homopolymeric or purely helical hairpin RNAs with low-nanomolar affinity, overturning the view that the RRM is required for recognition.\",\n      \"method\": \"Solution NMR structure determination, chemical shift perturbation, solvent PRE, intermolecular NOEs, mutagenesis, RNA binding assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.22.652967\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARP6 binds ZNF267 mRNA and regulates its stability and translation in colorectal cancer cells. Reduced ZNF267 by LARP6 inhibits downstream SGMS2 expression, causing ceramide/sphingomyelin imbalance and enhanced autophagy, thereby suppressing CRC progression.\",\n      \"method\": \"RIP-seq, RIP-qPCR, stable overexpression/knockdown, mRNA stability assay, autophagy assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP-seq identifies binding, functional cascade validated by KD/OE with multiple readouts; single lab\",\n      \"pmids\": [\"36691044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In MDA-MB-231 triple-negative breast cancer cells, LARP6 directly binds mRNAs (iRIP-seq identifies CGACGAG binding motif) and regulates alternative splicing of >1000 events, with regulated genes enriched in DNA repair and cell cycle pathways, promoting cancer cell proliferation and invasion.\",\n      \"method\": \"iRIP-seq, RNA-seq, RT-qPCR, RIP-qPCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — iRIP-seq identifies direct binding with motif; functional link to AS regulation shown; single lab\",\n      \"pmids\": [\"40050364\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LARP6 is an RNA-binding protein that uses its La domain (specifically the RNK motif) and flanking RRM1—with the N-terminal IDR restricting binding selectivity—to sequence-specifically recognize a conserved 5' stem-loop in the 5'UTR of type I and III collagen mRNAs, thereby targeting these mRNAs to the ER membrane (via interactions with SEC61 translocon and nonmuscle myosin filaments), regulating their translation in a coordinated manner facilitated by accessory proteins STRAP and FKBP3; LARP6 activity is post-translationally tuned by hierarchical phosphorylation at S451 (Akt) and S348/S409 (mTORC1), and LARP6 additionally functions in ciliogenesis by binding α-tubulin mRNA within DNAAF6-containing biomolecular condensates in multiciliated cells, and more broadly regulates alternative splicing and translation of hundreds of mRNAs in cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LARP6 is an RNA-binding protein that orchestrates collagen biosynthesis by sequence-specifically recognizing a conserved 5′ stem-loop (5′SL) in the 5′UTR of type I and type III collagen mRNAs and directing their coordinated translation at the ER membrane. High-affinity 5′SL recognition (~1.4 nM Kd) is conferred by an RNK motif within the La domain, with the adjacent RRM1 stabilizing the complex and an N-terminal intrinsically disordered region restricting RNA-binding selectivity; LARP6 targets collagen mRNAs to SEC61 translocons via its RRM loop 3 and cooperates with nonmuscle myosin filaments to partition these mRNAs at the ER independently of translation [PMID:19917293, PMID:25488812, PMID:34896113, PMID:25692237, PMID:25271881, PMID:41714637]. LARP6 activity is tuned by hierarchical phosphorylation—Akt at S451 and mTORC1 at S348/S409—which regulates interaction with the accessory protein STRAP, ER membrane cycling, and proper collagen folding and secretion [PMID:26932461, PMID:28112218]. Beyond collagen, LARP6 functions in ciliogenesis by binding α-tubulin mRNA within DNAAF6-containing biomolecular condensates in multiciliated cells, and genome-wide eCLIP/iCLIP studies reveal it interacts with hundreds of mRNAs, regulating translation and alternative splicing in contexts including hepatic stellate cell activation and cancer [PMID:38762183, PMID:41746718, PMID:40050364].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that LARP6 is a sequence-specific collagen mRNA-binding protein resolved how type I collagen mRNAs are distinguished from bulk mRNAs for specialized translational regulation at the ER.\",\n      \"evidence\": \"Biochemical binding assays (Kd ~1.4 nM), siRNA knockdown, polysome fractionation, and collagen-GFP reporter imaging in human fibroblasts\",\n      \"pmids\": [\"19917293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of 5′SL recognition unknown\", \"Mechanism coupling LARP6 binding to ER membrane targeting not addressed\", \"Physiological relevance in vivo not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of FKBP3 as a LARP6-interacting protein showed that accessory factors modulate collagen mRNA engagement, and that pharmacological disruption (FK506) of this interaction blocks fibrosis in vivo.\",\n      \"evidence\": \"Co-immunoprecipitation, RNA pull-down, and in vivo fibrosis model with FK506 treatment\",\n      \"pmids\": [\"23755290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. bridged interaction between FKBP3 and LARP6 not resolved\", \"Single-lab observation without independent replication\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural and mutagenesis studies defined the bipartite La–RRM1 architecture required for 5′SL recognition and simultaneously revealed that LARP6 bridges collagen mRNAs to SEC61 translocons and the ER membrane via nonmuscle myosin filaments, establishing the mechanism of mRNA-to-translocon targeting.\",\n      \"evidence\": \"X-ray/NMR structures of LaM and RRM1, mutagenesis, gel-shift assays, dominant-negative SEC61-interaction-deficient mutant, subcellular fractionation, and myosin depolymerization in fibroblasts\",\n      \"pmids\": [\"25488812\", \"25692237\", \"25271881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of LARP6 bound to 5′SL RNA\", \"Direct binding interface between LARP6 and SEC61 not mapped at residue level\", \"Role of nonmuscle myosin remains correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that IGF-1 stimulates collagen synthesis through PI3K/Akt-dependent increase in LARP6 expression and collagen mRNA loading placed LARP6 downstream of growth factor signaling.\",\n      \"evidence\": \"RIP-qPCR, 5′SL mutation and RNA decoy sequestration, PI3K/Akt pathway inhibitors in fibroblasts\",\n      \"pmids\": [\"24469459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional vs. post-transcriptional regulation of LARP6 levels by IGF-1 not fully dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping Akt phosphorylation of LARP6 at S451 as a hierarchical prerequisite for subsequent phosphorylation events established that post-translational modification directly controls collagen folding and secretion quality.\",\n      \"evidence\": \"Mass spectrometry phosphosite mapping, PI3K/Akt inhibitors, S451A dominant-negative mutant, pulse-chase secretion assay in lung fibroblasts\",\n      \"pmids\": [\"26932461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of downstream kinases phosphorylating other serines (beyond mTORC1) not fully resolved\", \"Phosphorylation-dependent structural changes in LARP6 not characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating mTORC1-dependent phosphorylation at S348/S409 explained how LARP6 cycles between ER-bound collagen mRNA complexes and soluble forms, coupling nutrient sensing to collagen production.\",\n      \"evidence\": \"Rapamycin treatment, raptor knockdown, S348A/S409A dominant-negative mutant, co-IP with STRAP, subcellular fractionation\",\n      \"pmids\": [\"28112218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal order of Akt vs. mTORC1 phosphorylation in a single translation cycle not resolved\", \"STRAP's molecular role in translation coordination unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pinpointing the RNK motif in the La domain as necessary and sufficient for 5′SL recognition refined the binding model and explained why other LARP family members cannot bind collagen mRNAs.\",\n      \"evidence\": \"UV-crosslinking mapping, domain deletion, mutagenesis, and RNA binding assays\",\n      \"pmids\": [\"34896113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the RNK–5′SL interface not yet available from peer-reviewed work\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that the prostaglandin D2 receptor CRTH2 binds LARP6's collagen mRNA recognition site and promotes collagen mRNA degradation identified an upstream negative regulator, with genetic epistasis confirming LARP6 as the downstream effector in fibrosis.\",\n      \"evidence\": \"Co-IP, CRTH2/LARP6 double depletion epistasis, caveolin-1-dependent trafficking, CRTH2 knockout mouse fibrosis model\",\n      \"pmids\": [\"34223653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CRTH2 binding to LARP6 triggers mRNA degradation unresolved\", \"Whether CRTH2–LARP6 interaction occurs on all collagen mRNA targets not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of ZNF267 mRNA as a non-collagen LARP6 target in colorectal cancer demonstrated LARP6 regulates mRNA stability and translation beyond collagens, linking it to ceramide/sphingomyelin balance and autophagy.\",\n      \"evidence\": \"RIP-seq, RIP-qPCR, stable knockdown/overexpression, mRNA stability and autophagy assays in CRC cells\",\n      \"pmids\": [\"36691044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LARP6 binds ZNF267 mRNA via a stem-loop analogous to collagen 5′SL is unknown\", \"Single-lab finding not independently replicated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that LARP6 localizes to DNAAF6-containing biomolecular condensates and binds α-tubulin mRNA in multiciliated cells extended LARP6 function to ciliogenesis, independent of collagen.\",\n      \"evidence\": \"Co-localization, co-IP, RNA binding assay, and DNAAF6 morphant rescue with binding-deficient mutant in Xenopus MCCs\",\n      \"pmids\": [\"38762183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA element in α-tubulin mRNA recognized by LARP6 not mapped\", \"Whether LARP6 functions in mammalian ciliogenesis not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that the N-terminal IDR restricts LARP6 RNA-binding selectivity and is required for cancer cell viability and invasion established a regulatory mechanism that explains how LARP6 discriminates among potential mRNA targets.\",\n      \"evidence\": \"In-cell MS RNA interaction mapping, iCLIP, IDR deletion mutagenesis, cancer cell invasion/viability assays\",\n      \"pmids\": [\"41714637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IDR–La module interaction not resolved at atomic level\", \"Whether IDR-mediated selectivity operates in normal (non-cancer) physiology not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"iRIP-seq in breast cancer cells revealed LARP6 binds a CGACGAG motif on >1000 mRNAs and regulates alternative splicing, expanding its functional repertoire beyond translational control.\",\n      \"evidence\": \"iRIP-seq with motif discovery, RNA-seq, RT-qPCR in MDA-MB-231 cells\",\n      \"pmids\": [\"40050364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which an RNA-binding protein regulates splicing not elucidated\", \"Overlap between iRIP-seq and eCLIP targets from other studies not assessed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Genome-wide eCLIP and ribosome profiling in activated hepatic stellate cells showed LARP6 interacts with >300 mRNAs and controls their translation, confirming broad translational regulatory scope in a disease-relevant fibrotic context.\",\n      \"evidence\": \"eCLIP, ribosome profiling, IP-mass spectrometry, snRNA-seq, ATAC-seq, HSC-specific siRNA knockdown\",\n      \"pmids\": [\"41746718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules distinguishing translationally regulated from non-regulated LARP6-bound mRNAs unknown\", \"Contribution of individual non-collagen targets to fibrosis phenotype not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A peer-reviewed atomic-resolution structure of the LARP6 La domain bound to 5′SL RNA and the mechanism by which LARP6 regulates alternative splicing remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No peer-reviewed co-structure of LARP6–5′SL complex\", \"Splicing regulatory mechanism entirely uncharacterized\", \"How LARP6 selectivity for collagen vs. non-collagen targets is determined genome-wide is unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 8, 10, 11, 12, 14, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009056\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SEC61A1\",\n      \"FKBP3\",\n      \"STRAP\",\n      \"DNAAF6\",\n      \"CRTH2\",\n      \"MYH9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}