{"gene":"MYL6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"MYL6 (ELC) is a component of non-muscle myosin II complexes, associating with myosin heavy chains MYH9 (NMHC IIA) and MYH10 (NMHC IIB) as well as regulatory light chains MYL12A, MYL12B, and MYL9 in NIH 3T3 fibroblasts. Knockdown of regulatory light chains MYL12A/12B caused significant reduction in MYL6 protein levels, indicating that RLC expression is required to maintain MYL6 stability within the myosin II complex.","method":"Proteomic association analysis (Co-IP/MS), siRNA knockdown with Western blot quantification in NIH 3T3 fibroblasts","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal proteomic association and knockdown with protein-level readout, single lab, two orthogonal methods","pmids":["21126233"],"is_preprint":false},{"year":1996,"finding":"MYL6 (MLC3nm, the nonmuscle essential light chain isoform) shows the lowest sarcomeric sorting specificity among alkali MLC isoforms when expressed in cardiomyocytes; it distributes throughout the cytoplasm rather than localizing to A-bands. The N-terminal lobe of each MLC isoprotein is responsible for isoform-specific sarcomeric sorting.","method":"Double epitope-tagging competition assay with confocal microscopy in adult and neonatal rat ventricular cardiomyocytes; chimeric cDNA expression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (sorting specificity), chimeric construct mutagenesis, single lab","pmids":["8856505"],"is_preprint":false},{"year":1990,"finding":"Human MYL6 encodes two closely related essential light chain isoforms (MLC1sa and MLC3nm) generated from the same gene via alternative splicing; in smooth muscle one exon is spliced out of the MLC3nm transcript to give an alternative product. MLC3nm is the major nonmuscle alkaline myosin light chain across multiple species. MLC1sa expression is detected at the onset of myogenesis and is present in nonmuscle cells.","method":"cDNA cloning and sequencing, isoform-specific probes, RNA expression analysis in multiple species and cell types, RT-PCR validation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization with multiple orthogonal methods, single lab, foundational isoform characterization","pmids":["2304459"],"is_preprint":false},{"year":2015,"finding":"SPATA6, a testis-specific protein required for sperm head-tail coupling apparatus (HTCA) assembly, interacts with myosin subunit MYL6, implicating MYL6 in myosin-based microfilament transport during spermiogenesis.","method":"Proteomic analysis of SPATA6-interacting proteins in mouse spermatids","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomic pulldown identifying MYL6 as an interaction partner of SPATA6, no functional follow-up specific to MYL6","pmids":["25605924"],"is_preprint":false},{"year":2024,"finding":"BAG5, a co-chaperone expressed in step 9-16 spermatids, is required for proper folding of MYL6 (along with MYO5A and dynein subunits) during sperm HTCA assembly. In BAG5-deficient mice, MYL6 and other cargo transport-related myosin proteins are misfolded, leading to acephalic spermatozoa syndrome. BAG5 promotes folding by forming a complex with HSPA8 and enhancing HSPA8's affinity for substrate proteins including MYL6.","method":"BAG5 knockout mouse model, in vivo and in vitro protein folding assays, co-immunoprecipitation, Western blot","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype, in vitro folding assays, co-IP; single lab with multiple orthogonal methods","pmids":["38454159"],"is_preprint":false},{"year":2024,"finding":"MYL6 interacts directly with kindlin-3 in platelets and is required for integrin αIIbβ3 activation, platelet aggregation, and proplatelet formation. Conditional knockout of Myl6 in the megakaryocyte lineage (Myl6fl/fl PF4-Cre mice) causes macrothrombocytopenia from defective proplatelet formation, suppresses integrin αIIbβ3 activation, and impairs hemostasis and thrombosis. MYL6 deficiency preferentially affected multivalent ligand binding to integrin αIIbβ3, suggesting MYL6 contributes to avidity modulation via kindlin-3.","method":"Conditional knockout mouse (Myl6fl/fl PF4-Cre), integrin activation assays, platelet aggregation assays, co-immunoprecipitation (kindlin-3 binding), hemostasis and thrombosis in vivo models","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular and in vivo phenotype, reciprocal interaction data, multiple orthogonal functional assays, single lab but comprehensive","pmids":["38266679"],"is_preprint":false},{"year":2022,"finding":"Anti-MYL6 antibody found in a subset of microscopic polyangiitis patients disrupts G-actin polymerization into F-actin, thereby suppressing phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap (NET) formation. This indicates that MYL6 is required for actin rearrangement necessary for NET formation in neutrophils.","method":"Fluorescent staining of actin polymerization and NET formation in neutrophils treated with anti-MYL6 antibody; ELISA for serum anti-MYL6 antibody; clinical correlation study","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (actin polymerization and NET formation inhibition by anti-MYL6 antibody), single lab, mechanistic follow-up","pmids":["36527167"],"is_preprint":false},{"year":2022,"finding":"ADCK2 overexpression in melanoma cells reduces cell migration, and this effect is abrogated by knockdown of MYL6, establishing a functional connection between ADCK2 and MYL6 in the regulation of melanoma cell motility. MYL6 acts downstream of ADCK2 to modulate cell migration.","method":"siRNA-mediated knockdown and stable overexpression of ADCK2; scratch assay; transwell invasion assay; MYL6 knockdown in ADCK2-overexpressing cells; gene expression array","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double knockdown with defined motility phenotype, single lab, two orthogonal migration assays","pmids":["35205819"],"is_preprint":false},{"year":2021,"finding":"The lncRNA MAFG-AS1 physically interacts with three subunits of non-muscle myosin IIA — MYH9, MYL12B, and MYL6. Knockdown of MAFG-AS1 inhibits ATPase activity of MYH9 and disrupts interaction of NM IIA subunits, indicating that MYL6 participates in the functional non-muscle myosin IIA complex whose activity is modulated by MAFG-AS1.","method":"RNA immunoprecipitation (RIP)/pulldown identifying MYL6 as an MAFG-AS1-interacting protein; ATPase activity assay after MAFG-AS1 knockdown; co-IP of NM IIA subunits","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, lncRNA-protein interaction pulldown, ATPase assay indirect; MYL6 is a secondary finding in a paper primarily about MAFG-AS1","pmids":["33813778"],"is_preprint":false},{"year":2009,"finding":"MYL6 was identified as a candidate interaction partner of PCBP1 (an hnRNP RNA-binding protein) by yeast two-hybrid screening, pulldown in yeast, co-immunoprecipitation, and immunofluorescence assays.","method":"Yeast two-hybrid, yeast pulldown, co-immunoprecipitation, immunofluorescence microscopy","journal":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple interaction methods but no functional consequence established for MYL6 specifically; single lab","pmids":["19727228"],"is_preprint":false},{"year":2024,"finding":"Myo5c (Myosin 5c) can be co-produced with MYL6 (essential light chain) and MYL12b (regulatory light chain) as well as calmodulin. Purified Myo5c-HMM produced with CaM plus MYL6/MYL12b retains actin-activated ATPase and motile activity, demonstrating that MYL6 can function as a light chain for Myosin 5c.","method":"Recombinant protein co-production and purification; in vitro actin-activated ATPase assay; motility assay","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with functional ATPase assay, but MYL6 role is ancillary to Myo5c characterization; single lab","pmids":["38606007"],"is_preprint":false},{"year":2026,"finding":"Phosphorylation of Tyr242 on cGAS facilitates its interaction with activated MYL6 in lung endothelial cells, enabling cGAS condensation and activation, leading to IFNB mRNA expression. Intracellular Ca2+ increase upon cGAS binding to dsDNA requires the ER Ca2+ sensor STIM1 to activate MYL6 for cGAS condensation. Expression of wild-type or phosphomimetic cGAS in cGAS-deficient mouse lung endothelium enhanced innate immune signaling and lung damage after Pseudomonas aeruginosa infection.","method":"Phosphomimetic/phospho-dead cGAS mutants, co-immunoprecipitation, cGAS condensation imaging, Ca2+ measurement, STIM1 perturbation, in vivo lung infection model with endothelium-specific cGAS rescue","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis, co-IP, reconstitution in cells, in vivo genetic rescue with multiple orthogonal methods in one study","pmids":["42154837"],"is_preprint":false},{"year":2025,"finding":"MYL6 is a pseudouridine-binding protein required for secretion of RNAs into extracellular vesicles. Genome-wide CRISPR screening and proteomics identified MYL6 as necessary for extracellular RNA export; pseudouridine modification of RNA is both necessary and sufficient for this export, and MYL6 reads this modification to direct RNA into extracellular routes.","method":"Genome-wide CRISPR screen, proteomics, high-sensitivity transcriptomics, pseudouridine-RNA binding assays, extracellular vesicle RNA profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus proteomic binding assays, single lab, preprint not yet peer-reviewed","pmids":["41280092"],"is_preprint":true},{"year":2026,"finding":"ARHGAP10-202aa, a protein encoded by the circRNA circARHGAP10, interacts with MYL6 and promotes myoblast differentiation. In vivo overexpression of ARHGAP10-202aa significantly enhances MYL6 expression and accelerates regeneration of injured tibialis anterior muscle in mice.","method":"Co-immunoprecipitation (ARHGAP10-202aa – MYL6 interaction), functional differentiation assays, in vivo muscle regeneration model with overexpression","journal":"Journal of genetics and genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP interaction with functional overexpression assay; MYL6 is a secondary interaction partner, mechanistic detail limited","pmids":["41617081"],"is_preprint":false},{"year":2025,"finding":"Under mechanical stretch simulating glomerular hypertension, murine podocytes undergo an isoform switch of Myl6 mRNAs accompanied by an alteration in the C-terminal amino acid sequence of the encoded protein, which is predicted to alter Myl6 interaction properties within the myosin complex.","method":"RNA-Seq with multiple splicing analysis tools, proteomics, quantitative RT-PCR, in situ hybridization in mechanically stretched murine podocytes","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic and proteomic analysis with orthogonal validation methods, direct demonstration of isoform switch with sequence consequence; single lab","pmids":["40418580"],"is_preprint":false}],"current_model":"MYL6 is an essential (alkali) light chain of myosin II and myosin V complexes that associates with non-muscle myosin heavy chains (MYH9, MYH10) to stabilize the holoenzyme; it shows isoform-specific subcellular sorting determined by its N-terminal lobe, undergoes tissue- and stress-specific alternative splicing that alters its C-terminal sequence and interaction properties, is required in platelets for kindlin-3-mediated integrin αIIbβ3 avidity regulation and proplatelet formation, supports actin rearrangement necessary for neutrophil extracellular trap formation, participates in cGAS condensation and innate immune activation in lung endothelium via a phospho-Tyr242-cGAS interaction, functions as a pseudouridine-binding protein that directs modified RNAs into extracellular vesicles, and requires the chaperone BAG5/HSPA8 axis for proper folding during sperm head-tail coupling apparatus assembly."},"narrative":{"mechanistic_narrative":"MYL6 is the essential (alkali) myosin light chain that integrates into non-muscle myosin II and class V myosin holoenzymes, where it associates with the heavy chains MYH9 and MYH10 and with regulatory light chains MYL12A/B and MYL9, and its stability within the complex depends on regulatory light chain expression [PMID:21126233]. Beyond its structural role in the holoenzyme, it can serve as a functional light chain for Myosin 5c, supporting actin-activated ATPase and motility in reconstituted complexes [PMID:38606007]. The MYL6 gene generates closely related essential light chain isoforms by alternative splicing, with isoform-specific N-terminal lobes dictating subcellular sorting and a stress-responsive C-terminal switch that alters interaction properties within the myosin complex [PMID:8856505, PMID:2304459, PMID:40418580]. Through its myosin-associated, actin-coupled activity MYL6 supports diverse cytoskeleton-dependent cellular processes: in the megakaryocyte/platelet lineage it binds kindlin-3 and is required for integrin αIIbβ3 avidity modulation, proplatelet formation, and hemostasis, with conditional knockout producing macrothrombocytopenia [PMID:38266679]; it enables the actin rearrangement underlying neutrophil extracellular trap formation [PMID:36527167]; and in lung endothelium it is activated downstream of STIM1-dependent Ca2+ signaling to engage phospho-Tyr242 cGAS, driving cGAS condensation and type I interferon innate immune signaling [PMID:42154837]. During spermiogenesis MYL6 requires the BAG5–HSPA8 chaperone axis for proper folding during assembly of the sperm head-tail coupling apparatus, and its misfolding causes acephalic spermatozoa [PMID:38454159].","teleology":[{"year":1990,"claim":"Established the molecular identity of MYL6 as a gene encoding multiple essential light chain isoforms generated by alternative splicing, defining the nonmuscle alkaline myosin light chain.","evidence":"cDNA cloning, isoform-specific probes, and RNA expression analysis across species and cell types","pmids":["2304459"],"confidence":"Medium","gaps":["Functional difference between MLC1sa and MLC3nm isoforms not resolved","No structural data on light chain–heavy chain binding"]},{"year":1996,"claim":"Resolved why MYL6 distributes diffusely rather than into sarcomeres, attributing isoform-specific sorting to the N-terminal lobe and establishing its nonmuscle character.","evidence":"Epitope-tagging competition assay with confocal microscopy and chimeric cDNA expression in rat cardiomyocytes","pmids":["8856505"],"confidence":"Medium","gaps":["Sorting determinant mapped to N-lobe but binding partners conferring specificity not identified","Studied in cardiomyocyte context only"]},{"year":2009,"claim":"Identified MYL6 as a candidate interaction partner of the RNA-binding protein PCBP1, an early hint of non-cytoskeletal associations.","evidence":"Yeast two-hybrid, yeast pulldown, co-IP, and immunofluorescence","pmids":["19727228"],"confidence":"Low","gaps":["No functional consequence established for the MYL6–PCBP1 interaction","Single lab, interaction screen only"]},{"year":2011,"claim":"Defined MYL6 as a stable component of the non-muscle myosin II complex and showed its protein stability depends on regulatory light chain expression.","evidence":"Co-IP/MS proteomic association and siRNA knockdown with Western blot in NIH 3T3 fibroblasts","pmids":["21126233"],"confidence":"Medium","gaps":["Stoichiometry within the holoenzyme not quantified","Whether RLC dependence holds in non-fibroblast cells untested"]},{"year":2015,"claim":"Linked MYL6 to spermiogenesis by identifying its interaction with the HTCA-assembly protein SPATA6, implicating myosin-based transport during sperm head-tail coupling.","evidence":"Proteomic analysis of SPATA6-interacting proteins in mouse spermatids","pmids":["25605924"],"confidence":"Low","gaps":["Single proteomic pulldown with no MYL6-specific functional follow-up","Direct vs indirect binding not distinguished"]},{"year":2021,"claim":"Reinforced MYL6 as a functional subunit of non-muscle myosin IIA whose activity can be modulated by an interacting lncRNA.","evidence":"RIP/pulldown, ATPase assay after MAFG-AS1 knockdown, and co-IP of NM IIA subunits","pmids":["33813778"],"confidence":"Low","gaps":["MYL6 a secondary finding; ATPase readout indirect for MYL6 role","Mechanism by which lncRNA tunes complex unclear"]},{"year":2022,"claim":"Demonstrated MYL6 is required for actin polymerization driving neutrophil extracellular trap formation, connecting it to innate immune effector function.","evidence":"Anti-MYL6 antibody inhibition of actin polymerization and NET formation in neutrophils; clinical correlation in microscopic polyangiitis","pmids":["36527167"],"confidence":"Medium","gaps":["Antibody-based loss of function; genetic confirmation absent","Molecular step between MYL6 and actin assembly not defined"]},{"year":2022,"claim":"Placed MYL6 downstream of ADCK2 in the control of melanoma cell migration via an epistasis experiment.","evidence":"ADCK2 overexpression and MYL6 knockdown with scratch and transwell migration assays","pmids":["35205819"],"confidence":"Medium","gaps":["Mechanistic link between ADCK2 and MYL6 not defined","Whether the effect operates through myosin contractility untested"]},{"year":2024,"claim":"Provided the strongest genetic evidence for MYL6 function: kindlin-3 binding and a requirement for integrin αIIbβ3 avidity, proplatelet formation, and hemostasis.","evidence":"Megakaryocyte-lineage conditional knockout mouse, integrin activation and aggregation assays, co-IP, and in vivo thrombosis models","pmids":["38266679"],"confidence":"High","gaps":["Structural basis of MYL6–kindlin-3 interaction unknown","How a myosin light chain regulates integrin avidity mechanistically unresolved"]},{"year":2024,"claim":"Established that MYL6 requires the BAG5–HSPA8 chaperone axis for folding during sperm head-tail coupling apparatus assembly, with misfolding causing acephalic spermatozoa.","evidence":"BAG5 knockout mouse, in vivo/in vitro folding assays, and co-IP","pmids":["38454159"],"confidence":"Medium","gaps":["Whether MYL6 misfolding alone causes the phenotype not isolated","Folding requirement in other tissues untested"]},{"year":2024,"claim":"Demonstrated by reconstitution that MYL6 can serve as the essential light chain for Myosin 5c, conferring actin-activated ATPase and motility.","evidence":"Recombinant co-production and purification with in vitro ATPase and motility assays","pmids":["38606007"],"confidence":"Medium","gaps":["MYL6 role ancillary to Myo5c characterization","Physiological context of MYL6–Myo5c pairing not addressed"]},{"year":2025,"claim":"Identified a glomerular-hypertension-responsive Myl6 isoform switch that alters the C-terminal sequence and predicted interaction properties, linking mechanical stress to myosin remodeling.","evidence":"RNA-Seq splicing analysis, proteomics, RT-PCR, and in situ hybridization in mechanically stretched murine podocytes","pmids":["40418580"],"confidence":"Medium","gaps":["Functional consequence of the C-terminal switch predicted, not measured","Whether the switch changes contractility unknown"]},{"year":2025,"claim":"Uncovered a non-myosin function for MYL6 as a pseudouridine-binding protein that directs modified RNAs into extracellular vesicles.","evidence":"Genome-wide CRISPR screen, proteomics, and pseudouridine-RNA binding assays (preprint)","pmids":["41280092"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How a myosin light chain reads RNA modifications structurally unexplained"]},{"year":2026,"claim":"Defined a signaling role for MYL6 in innate immunity: STIM1/Ca2+-activated MYL6 engages phospho-Tyr242 cGAS to drive cGAS condensation and type I interferon responses in lung endothelium.","evidence":"Phosphomimetic/phospho-dead cGAS mutants, co-IP, condensation imaging, Ca2+ measurement, STIM1 perturbation, and in vivo endothelium-specific cGAS rescue in lung infection","pmids":["42154837"],"confidence":"High","gaps":["Whether MYL6's myosin/actin activity is required for cGAS condensation unresolved","Direct vs scaffolded contact with cGAS not structurally defined"]},{"year":2026,"claim":"Linked MYL6 to myoblast differentiation through interaction with a circRNA-encoded micropeptide that upregulates MYL6 and accelerates muscle regeneration.","evidence":"Co-IP of ARHGAP10-202aa with MYL6 and in vivo muscle regeneration overexpression model","pmids":["41617081"],"confidence":"Low","gaps":["Single Co-IP; MYL6 a secondary partner","Causal role of MYL6 in the differentiation phenotype not isolated"]},{"year":null,"claim":"How a single essential myosin light chain coordinates its canonical structural role with emerging non-cytoskeletal activities (RNA modification reading, cGAS-coupled signaling, integrin avidity control) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model distinguishing myosin-bound vs free MYL6 functional states","Mechanism by which isoform/splice variants partition among these roles unknown","Whether non-myosin functions require myosin binding untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,6,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,11]}],"complexes":["non-muscle myosin IIA","Myosin 5c holoenzyme"],"partners":["MYH9","MYH10","MYL12A","MYL12B","KINDLIN-3","CGAS","SPATA6","HSPA8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60660","full_name":"Myosin light polypeptide 6","aliases":["17 kDa myosin light chain","LC17","Myosin light chain 3","MLC-3","Myosin light chain alkali 3","Myosin light chain A3","Smooth muscle and nonmuscle myosin light chain alkali 6"],"length_aa":151,"mass_kda":16.9,"function":"Regulatory light chain of myosin. Does not bind calcium","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P60660/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYL6","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000092841","cell_line_id":"CID001437","localizations":[{"compartment":"cytoskeleton","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"CALM1","stoichiometry":10.0},{"gene":"CALM2","stoichiometry":10.0},{"gene":"CALM3","stoichiometry":10.0},{"gene":"CDC42","stoichiometry":10.0},{"gene":"MYH9","stoichiometry":10.0},{"gene":"MYL6B","stoichiometry":10.0},{"gene":"CALM2;CALM3;CALM1","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"MYH10","stoichiometry":0.2},{"gene":"MYL12A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001437","total_profiled":1310},"omim":[{"mim_id":"615936","title":"RHO GTPase-ACTIVATING PROTEIN 42; ARHGAP42","url":"https://www.omim.org/entry/615936"},{"mim_id":"609931","title":"MYOSIN LIGHT CHAIN 6, ALKALI, SMOOTH MUSCLE AND NONMUSCLE; MYL6","url":"https://www.omim.org/entry/609931"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYL6"},"hgnc":{"alias_symbol":["ESMLC","MLC3NM","MLC1SM"],"prev_symbol":[]},"alphafold":{"accession":"P60660","domains":[{"cath_id":"1.10.238.10","chopping":"5-78","consensus_level":"high","plddt":95.8112,"start":5,"end":78},{"cath_id":"1.10.238.10","chopping":"85-148","consensus_level":"high","plddt":96.4184,"start":85,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60660","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60660-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60660-F1-predicted_aligned_error_v6.png","plddt_mean":95.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYL6","jax_strain_url":"https://www.jax.org/strain/search?query=MYL6"},"sequence":{"accession":"P60660","fasta_url":"https://rest.uniprot.org/uniprotkb/P60660.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60660/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60660"}},"corpus_meta":[{"pmid":"31669095","id":"PMC_31669095","title":"Shared 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Knockdown of regulatory light chains MYL12A/12B caused significant reduction in MYL6 protein levels, indicating that RLC expression is required to maintain MYL6 stability within the myosin II complex.\",\n      \"method\": \"Proteomic association analysis (Co-IP/MS), siRNA knockdown with Western blot quantification in NIH 3T3 fibroblasts\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal proteomic association and knockdown with protein-level readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"21126233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"MYL6 (MLC3nm, the nonmuscle essential light chain isoform) shows the lowest sarcomeric sorting specificity among alkali MLC isoforms when expressed in cardiomyocytes; it distributes throughout the cytoplasm rather than localizing to A-bands. The N-terminal lobe of each MLC isoprotein is responsible for isoform-specific sarcomeric sorting.\",\n      \"method\": \"Double epitope-tagging competition assay with confocal microscopy in adult and neonatal rat ventricular cardiomyocytes; chimeric cDNA expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (sorting specificity), chimeric construct mutagenesis, single lab\",\n      \"pmids\": [\"8856505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Human MYL6 encodes two closely related essential light chain isoforms (MLC1sa and MLC3nm) generated from the same gene via alternative splicing; in smooth muscle one exon is spliced out of the MLC3nm transcript to give an alternative product. MLC3nm is the major nonmuscle alkaline myosin light chain across multiple species. MLC1sa expression is detected at the onset of myogenesis and is present in nonmuscle cells.\",\n      \"method\": \"cDNA cloning and sequencing, isoform-specific probes, RNA expression analysis in multiple species and cell types, RT-PCR validation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization with multiple orthogonal methods, single lab, foundational isoform characterization\",\n      \"pmids\": [\"2304459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPATA6, a testis-specific protein required for sperm head-tail coupling apparatus (HTCA) assembly, interacts with myosin subunit MYL6, implicating MYL6 in myosin-based microfilament transport during spermiogenesis.\",\n      \"method\": \"Proteomic analysis of SPATA6-interacting proteins in mouse spermatids\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomic pulldown identifying MYL6 as an interaction partner of SPATA6, no functional follow-up specific to MYL6\",\n      \"pmids\": [\"25605924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAG5, a co-chaperone expressed in step 9-16 spermatids, is required for proper folding of MYL6 (along with MYO5A and dynein subunits) during sperm HTCA assembly. In BAG5-deficient mice, MYL6 and other cargo transport-related myosin proteins are misfolded, leading to acephalic spermatozoa syndrome. BAG5 promotes folding by forming a complex with HSPA8 and enhancing HSPA8's affinity for substrate proteins including MYL6.\",\n      \"method\": \"BAG5 knockout mouse model, in vivo and in vitro protein folding assays, co-immunoprecipitation, Western blot\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype, in vitro folding assays, co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38454159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYL6 interacts directly with kindlin-3 in platelets and is required for integrin αIIbβ3 activation, platelet aggregation, and proplatelet formation. Conditional knockout of Myl6 in the megakaryocyte lineage (Myl6fl/fl PF4-Cre mice) causes macrothrombocytopenia from defective proplatelet formation, suppresses integrin αIIbβ3 activation, and impairs hemostasis and thrombosis. MYL6 deficiency preferentially affected multivalent ligand binding to integrin αIIbβ3, suggesting MYL6 contributes to avidity modulation via kindlin-3.\",\n      \"method\": \"Conditional knockout mouse (Myl6fl/fl PF4-Cre), integrin activation assays, platelet aggregation assays, co-immunoprecipitation (kindlin-3 binding), hemostasis and thrombosis in vivo models\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular and in vivo phenotype, reciprocal interaction data, multiple orthogonal functional assays, single lab but comprehensive\",\n      \"pmids\": [\"38266679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Anti-MYL6 antibody found in a subset of microscopic polyangiitis patients disrupts G-actin polymerization into F-actin, thereby suppressing phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap (NET) formation. This indicates that MYL6 is required for actin rearrangement necessary for NET formation in neutrophils.\",\n      \"method\": \"Fluorescent staining of actin polymerization and NET formation in neutrophils treated with anti-MYL6 antibody; ELISA for serum anti-MYL6 antibody; clinical correlation study\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (actin polymerization and NET formation inhibition by anti-MYL6 antibody), single lab, mechanistic follow-up\",\n      \"pmids\": [\"36527167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADCK2 overexpression in melanoma cells reduces cell migration, and this effect is abrogated by knockdown of MYL6, establishing a functional connection between ADCK2 and MYL6 in the regulation of melanoma cell motility. MYL6 acts downstream of ADCK2 to modulate cell migration.\",\n      \"method\": \"siRNA-mediated knockdown and stable overexpression of ADCK2; scratch assay; transwell invasion assay; MYL6 knockdown in ADCK2-overexpressing cells; gene expression array\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double knockdown with defined motility phenotype, single lab, two orthogonal migration assays\",\n      \"pmids\": [\"35205819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA MAFG-AS1 physically interacts with three subunits of non-muscle myosin IIA — MYH9, MYL12B, and MYL6. Knockdown of MAFG-AS1 inhibits ATPase activity of MYH9 and disrupts interaction of NM IIA subunits, indicating that MYL6 participates in the functional non-muscle myosin IIA complex whose activity is modulated by MAFG-AS1.\",\n      \"method\": \"RNA immunoprecipitation (RIP)/pulldown identifying MYL6 as an MAFG-AS1-interacting protein; ATPase activity assay after MAFG-AS1 knockdown; co-IP of NM IIA subunits\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, lncRNA-protein interaction pulldown, ATPase assay indirect; MYL6 is a secondary finding in a paper primarily about MAFG-AS1\",\n      \"pmids\": [\"33813778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MYL6 was identified as a candidate interaction partner of PCBP1 (an hnRNP RNA-binding protein) by yeast two-hybrid screening, pulldown in yeast, co-immunoprecipitation, and immunofluorescence assays.\",\n      \"method\": \"Yeast two-hybrid, yeast pulldown, co-immunoprecipitation, immunofluorescence microscopy\",\n      \"journal\": \"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple interaction methods but no functional consequence established for MYL6 specifically; single lab\",\n      \"pmids\": [\"19727228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myo5c (Myosin 5c) can be co-produced with MYL6 (essential light chain) and MYL12b (regulatory light chain) as well as calmodulin. Purified Myo5c-HMM produced with CaM plus MYL6/MYL12b retains actin-activated ATPase and motile activity, demonstrating that MYL6 can function as a light chain for Myosin 5c.\",\n      \"method\": \"Recombinant protein co-production and purification; in vitro actin-activated ATPase assay; motility assay\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with functional ATPase assay, but MYL6 role is ancillary to Myo5c characterization; single lab\",\n      \"pmids\": [\"38606007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Phosphorylation of Tyr242 on cGAS facilitates its interaction with activated MYL6 in lung endothelial cells, enabling cGAS condensation and activation, leading to IFNB mRNA expression. Intracellular Ca2+ increase upon cGAS binding to dsDNA requires the ER Ca2+ sensor STIM1 to activate MYL6 for cGAS condensation. Expression of wild-type or phosphomimetic cGAS in cGAS-deficient mouse lung endothelium enhanced innate immune signaling and lung damage after Pseudomonas aeruginosa infection.\",\n      \"method\": \"Phosphomimetic/phospho-dead cGAS mutants, co-immunoprecipitation, cGAS condensation imaging, Ca2+ measurement, STIM1 perturbation, in vivo lung infection model with endothelium-specific cGAS rescue\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis, co-IP, reconstitution in cells, in vivo genetic rescue with multiple orthogonal methods in one study\",\n      \"pmids\": [\"42154837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYL6 is a pseudouridine-binding protein required for secretion of RNAs into extracellular vesicles. Genome-wide CRISPR screening and proteomics identified MYL6 as necessary for extracellular RNA export; pseudouridine modification of RNA is both necessary and sufficient for this export, and MYL6 reads this modification to direct RNA into extracellular routes.\",\n      \"method\": \"Genome-wide CRISPR screen, proteomics, high-sensitivity transcriptomics, pseudouridine-RNA binding assays, extracellular vesicle RNA profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus proteomic binding assays, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41280092\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ARHGAP10-202aa, a protein encoded by the circRNA circARHGAP10, interacts with MYL6 and promotes myoblast differentiation. In vivo overexpression of ARHGAP10-202aa significantly enhances MYL6 expression and accelerates regeneration of injured tibialis anterior muscle in mice.\",\n      \"method\": \"Co-immunoprecipitation (ARHGAP10-202aa – MYL6 interaction), functional differentiation assays, in vivo muscle regeneration model with overexpression\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP interaction with functional overexpression assay; MYL6 is a secondary interaction partner, mechanistic detail limited\",\n      \"pmids\": [\"41617081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under mechanical stretch simulating glomerular hypertension, murine podocytes undergo an isoform switch of Myl6 mRNAs accompanied by an alteration in the C-terminal amino acid sequence of the encoded protein, which is predicted to alter Myl6 interaction properties within the myosin complex.\",\n      \"method\": \"RNA-Seq with multiple splicing analysis tools, proteomics, quantitative RT-PCR, in situ hybridization in mechanically stretched murine podocytes\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic and proteomic analysis with orthogonal validation methods, direct demonstration of isoform switch with sequence consequence; single lab\",\n      \"pmids\": [\"40418580\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYL6 is an essential (alkali) light chain of myosin II and myosin V complexes that associates with non-muscle myosin heavy chains (MYH9, MYH10) to stabilize the holoenzyme; it shows isoform-specific subcellular sorting determined by its N-terminal lobe, undergoes tissue- and stress-specific alternative splicing that alters its C-terminal sequence and interaction properties, is required in platelets for kindlin-3-mediated integrin αIIbβ3 avidity regulation and proplatelet formation, supports actin rearrangement necessary for neutrophil extracellular trap formation, participates in cGAS condensation and innate immune activation in lung endothelium via a phospho-Tyr242-cGAS interaction, functions as a pseudouridine-binding protein that directs modified RNAs into extracellular vesicles, and requires the chaperone BAG5/HSPA8 axis for proper folding during sperm head-tail coupling apparatus assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYL6 is the essential (alkali) myosin light chain that integrates into non-muscle myosin II and class V myosin holoenzymes, where it associates with the heavy chains MYH9 and MYH10 and with regulatory light chains MYL12A/B and MYL9, and its stability within the complex depends on regulatory light chain expression [#0]. Beyond its structural role in the holoenzyme, it can serve as a functional light chain for Myosin 5c, supporting actin-activated ATPase and motility in reconstituted complexes [#10]. The MYL6 gene generates closely related essential light chain isoforms by alternative splicing, with isoform-specific N-terminal lobes dictating subcellular sorting and a stress-responsive C-terminal switch that alters interaction properties within the myosin complex [#1, #2, #14]. Through its myosin-associated, actin-coupled activity MYL6 supports diverse cytoskeleton-dependent cellular processes: in the megakaryocyte/platelet lineage it binds kindlin-3 and is required for integrin \\u03b1IIb\\u03b23 avidity modulation, proplatelet formation, and hemostasis, with conditional knockout producing macrothrombocytopenia [#5]; it enables the actin rearrangement underlying neutrophil extracellular trap formation [#6]; and in lung endothelium it is activated downstream of STIM1-dependent Ca2+ signaling to engage phospho-Tyr242 cGAS, driving cGAS condensation and type I interferon innate immune signaling [#11]. During spermiogenesis MYL6 requires the BAG5\\u2013HSPA8 chaperone axis for proper folding during assembly of the sperm head-tail coupling apparatus, and its misfolding causes acephalic spermatozoa [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established the molecular identity of MYL6 as a gene encoding multiple essential light chain isoforms generated by alternative splicing, defining the nonmuscle alkaline myosin light chain.\",\n      \"evidence\": \"cDNA cloning, isoform-specific probes, and RNA expression analysis across species and cell types\",\n      \"pmids\": [\"2304459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between MLC1sa and MLC3nm isoforms not resolved\", \"No structural data on light chain\\u2013heavy chain binding\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved why MYL6 distributes diffusely rather than into sarcomeres, attributing isoform-specific sorting to the N-terminal lobe and establishing its nonmuscle character.\",\n      \"evidence\": \"Epitope-tagging competition assay with confocal microscopy and chimeric cDNA expression in rat cardiomyocytes\",\n      \"pmids\": [\"8856505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sorting determinant mapped to N-lobe but binding partners conferring specificity not identified\", \"Studied in cardiomyocyte context only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified MYL6 as a candidate interaction partner of the RNA-binding protein PCBP1, an early hint of non-cytoskeletal associations.\",\n      \"evidence\": \"Yeast two-hybrid, yeast pulldown, co-IP, and immunofluorescence\",\n      \"pmids\": [\"19727228\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence established for the MYL6\\u2013PCBP1 interaction\", \"Single lab, interaction screen only\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined MYL6 as a stable component of the non-muscle myosin II complex and showed its protein stability depends on regulatory light chain expression.\",\n      \"evidence\": \"Co-IP/MS proteomic association and siRNA knockdown with Western blot in NIH 3T3 fibroblasts\",\n      \"pmids\": [\"21126233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry within the holoenzyme not quantified\", \"Whether RLC dependence holds in non-fibroblast cells untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked MYL6 to spermiogenesis by identifying its interaction with the HTCA-assembly protein SPATA6, implicating myosin-based transport during sperm head-tail coupling.\",\n      \"evidence\": \"Proteomic analysis of SPATA6-interacting proteins in mouse spermatids\",\n      \"pmids\": [\"25605924\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single proteomic pulldown with no MYL6-specific functional follow-up\", \"Direct vs indirect binding not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced MYL6 as a functional subunit of non-muscle myosin IIA whose activity can be modulated by an interacting lncRNA.\",\n      \"evidence\": \"RIP/pulldown, ATPase assay after MAFG-AS1 knockdown, and co-IP of NM IIA subunits\",\n      \"pmids\": [\"33813778\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"MYL6 a secondary finding; ATPase readout indirect for MYL6 role\", \"Mechanism by which lncRNA tunes complex unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated MYL6 is required for actin polymerization driving neutrophil extracellular trap formation, connecting it to innate immune effector function.\",\n      \"evidence\": \"Anti-MYL6 antibody inhibition of actin polymerization and NET formation in neutrophils; clinical correlation in microscopic polyangiitis\",\n      \"pmids\": [\"36527167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody-based loss of function; genetic confirmation absent\", \"Molecular step between MYL6 and actin assembly not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed MYL6 downstream of ADCK2 in the control of melanoma cell migration via an epistasis experiment.\",\n      \"evidence\": \"ADCK2 overexpression and MYL6 knockdown with scratch and transwell migration assays\",\n      \"pmids\": [\"35205819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ADCK2 and MYL6 not defined\", \"Whether the effect operates through myosin contractility untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the strongest genetic evidence for MYL6 function: kindlin-3 binding and a requirement for integrin \\u03b1IIb\\u03b23 avidity, proplatelet formation, and hemostasis.\",\n      \"evidence\": \"Megakaryocyte-lineage conditional knockout mouse, integrin activation and aggregation assays, co-IP, and in vivo thrombosis models\",\n      \"pmids\": [\"38266679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MYL6\\u2013kindlin-3 interaction unknown\", \"How a myosin light chain regulates integrin avidity mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that MYL6 requires the BAG5\\u2013HSPA8 chaperone axis for folding during sperm head-tail coupling apparatus assembly, with misfolding causing acephalic spermatozoa.\",\n      \"evidence\": \"BAG5 knockout mouse, in vivo/in vitro folding assays, and co-IP\",\n      \"pmids\": [\"38454159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MYL6 misfolding alone causes the phenotype not isolated\", \"Folding requirement in other tissues untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated by reconstitution that MYL6 can serve as the essential light chain for Myosin 5c, conferring actin-activated ATPase and motility.\",\n      \"evidence\": \"Recombinant co-production and purification with in vitro ATPase and motility assays\",\n      \"pmids\": [\"38606007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYL6 role ancillary to Myo5c characterization\", \"Physiological context of MYL6\\u2013Myo5c pairing not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a glomerular-hypertension-responsive Myl6 isoform switch that alters the C-terminal sequence and predicted interaction properties, linking mechanical stress to myosin remodeling.\",\n      \"evidence\": \"RNA-Seq splicing analysis, proteomics, RT-PCR, and in situ hybridization in mechanically stretched murine podocytes\",\n      \"pmids\": [\"40418580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the C-terminal switch predicted, not measured\", \"Whether the switch changes contractility unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-myosin function for MYL6 as a pseudouridine-binding protein that directs modified RNAs into extracellular vesicles.\",\n      \"evidence\": \"Genome-wide CRISPR screen, proteomics, and pseudouridine-RNA binding assays (preprint)\",\n      \"pmids\": [\"41280092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How a myosin light chain reads RNA modifications structurally unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a signaling role for MYL6 in innate immunity: STIM1/Ca2+-activated MYL6 engages phospho-Tyr242 cGAS to drive cGAS condensation and type I interferon responses in lung endothelium.\",\n      \"evidence\": \"Phosphomimetic/phospho-dead cGAS mutants, co-IP, condensation imaging, Ca2+ measurement, STIM1 perturbation, and in vivo endothelium-specific cGAS rescue in lung infection\",\n      \"pmids\": [\"42154837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYL6's myosin/actin activity is required for cGAS condensation unresolved\", \"Direct vs scaffolded contact with cGAS not structurally defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked MYL6 to myoblast differentiation through interaction with a circRNA-encoded micropeptide that upregulates MYL6 and accelerates muscle regeneration.\",\n      \"evidence\": \"Co-IP of ARHGAP10-202aa with MYL6 and in vivo muscle regeneration overexpression model\",\n      \"pmids\": [\"41617081\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP; MYL6 a secondary partner\", \"Causal role of MYL6 in the differentiation phenotype not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single essential myosin light chain coordinates its canonical structural role with emerging non-cytoskeletal activities (RNA modification reading, cGAS-coupled signaling, integrin avidity control) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model distinguishing myosin-bound vs free MYL6 functional states\", \"Mechanism by which isoform/splice variants partition among these roles unknown\", \"Whether non-myosin functions require myosin binding untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 11]}\n    ],\n    \"complexes\": [\n      \"non-muscle myosin IIA\",\n      \"Myosin 5c holoenzyme\"\n    ],\n    \"partners\": [\n      \"MYH9\",\n      \"MYH10\",\n      \"MYL12A\",\n      \"MYL12B\",\n      \"kindlin-3\",\n      \"cGAS\",\n      \"SPATA6\",\n      \"HSPA8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}