{"gene":"ANXA11","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structures from FTLD-TDP type C patient brains revealed that ANXA11 co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains, with an extensive hydrophobic interface at the centre. The majority of ANXA11 in these filaments exists as an ~22 kDa N-terminal fragment lacking the annexin core domain.","method":"Cryo-electron microscopy structure determination from patient brain tissue, immunoblotting, immunohistochemistry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with atomic-level detail from patient tissue, validated by immunoblot and IHC, peer-reviewed in Nature and independently confirmed by preprint (PMID:38979278)","pmids":["39260416","38979278"],"is_preprint":false},{"year":2025,"finding":"ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. Changes to the protein phase state driven by the low-complexity ANXA11 N-terminus induce a coupled phase-state change in the lipids of the underlying lysosomal membrane. The ANXA11-interacting proteins ALG2 and CALC were identified as potent regulators of this ANXA11-based protein-lipid phase coupling, influencing the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules.","method":"Live-cell imaging, biophysical assays (nanomechanics), identification of interacting proteins (ALG2, CALC), co-trafficking experiments, loss-of-function studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biophysics, live imaging, interaction studies), replicated in both preprint and peer-reviewed publication by same group (PMID:36993242, PMID:40118863)","pmids":["40118863","36993242"],"is_preprint":false},{"year":2020,"finding":"ANXA11 regulates intracellular Ca2+ homeostasis and stress granule dynamics. ALS-associated N-terminal low-complexity domain variants (p.G38R, p.D40G) enhanced aggregation propensity and underwent abnormal phase separation, while C-terminal ANX domain variants (p.H390P, p.R456H) altered Ca2+ responses. All four variants caused alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. Ca2+-dependent interaction and co-aggregation between ANXA11 and ALS-causative RNA-binding proteins FUS and hnRNPA1 were observed in motor neuron cells and in brain from an ALS-FUS patient. ALS-linked ANXA11 variants caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis.","method":"Exome sequencing of ALS patients, Ca2+ imaging, stress granule assays, phase separation assays, Co-immunoprecipitation, immunofluorescence in motor neuron cells and patient brain tissue, apoptosis assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional methods (Ca2+ imaging, phase separation, Co-IP, patient brain tissue validation) in a single rigorous study","pmids":["33087501"],"is_preprint":false},{"year":2025,"finding":"Ca2+ acts as a master regulator of ANXA11 physiological function by modulating its conformational states. In the absence of Ca2+, the N-terminal (Nt) and C-terminal (Ct) domains interact with each other in a closed state. In the presence of Ca2+, this self-interaction is disrupted (open state), allowing both domains to interact with RNA and liposomes simultaneously. The ALS-associated p.D40G mutation in the Nt domain destabilizes interdomain interactions and bypasses Ca2+ regulation, leading to aberrant aggregation.","method":"In vitro biophysical assays with recombinant ANXA11 domain constructs, liposome binding assays, RNA binding assays, conformational analysis, mutagenesis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with mutagenesis, but preprint only, single lab","pmids":["bio_10.1101_2025.10.27.684738"],"is_preprint":true},{"year":2025,"finding":"In a p.P36R knock-in mouse model, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions in motor neurons and cortical neurons from 2 months of age. Autophagic flux was intact at 2 months but impaired by 9 months (decreased Beclin-1 and LC3BII/I, increased SQSTM1/p62, mTORC1 hyperactivation). Significant motor neuron loss and neuroinflammation were detected by 9 months. These findings implicate gain-of-function ANXA11 mutation in late-onset motor neuron disease via proteinopathy, neurodegeneration, neuroinflammation, and autophagic dysfunction.","method":"Knock-in mouse model (p.P36R), immunofluorescence, electron microscopy, autophagy flux assays, western blot, behavioral assessment","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in model with multiple orthogonal readouts (EM, biochemistry, behavior, histopathology), single lab","pmids":["39755715"],"is_preprint":false},{"year":2024,"finding":"ANXA11 and CHMP2B act sequentially in plasma membrane repair. Annexins (including ANXA11) are recruited immediately to sites of membrane damage (sealing phase), while ESCRT-III assembles only after membrane sealing to shed damaged membranes. FTD- and ALS-associated mutations in ANXA11 compromise the membrane repair process.","method":"Live-cell imaging of membrane damage and repair, temporal recruitment assays, loss-of-function with ALS/FTD mutants","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — live imaging with temporal resolution and mutant validation, but preprint only, single lab","pmids":["bio_10.1101_2024.11.19.624330"],"is_preprint":true},{"year":2023,"finding":"ANXA11 variants at Asp40 position (p.D40G, p.D40Y, p.D40Ile) share a common pathophysiology: in vitro studies using recombinant ANXA11 proteins showed abnormal phase separation, with p.D40Ile being more aggregation-prone than p.D40G. Patient fibroblasts with Asp40 variants exhibited defects in stress granule dynamics and clearance. Muscle histopathology showed ANXA11 protein aggregates, with super-resolution imaging revealing distinct aggregate structures in the sarcoplasm.","method":"Recombinant protein phase separation assays, patient fibroblast stress granule dynamics, muscle biopsy histopathology, super-resolution imaging","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with recombinant proteins plus patient-derived fibroblast and tissue validation, single lab","pmids":["36651622"],"is_preprint":false},{"year":2022,"finding":"Patient fibroblasts carrying FTD-linked ANXA11 variants p.P36R and p.D40G showed impaired intracellular calcium homeostasis, defective stress granule disassembly, and impaired protein translation.","method":"Calcium imaging, stress granule dynamics assays, protein translation assays in patient-derived fibroblasts","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts in patient-derived cells, single lab, corroborates prior findings in PMID:33087501","pmids":["36458208"],"is_preprint":false},{"year":2025,"finding":"ANXA11 is upregulated in regenerative MYH3+ myofibers in mdx mice and DMD patients and disrupts maturation of regenerative myofibers via dysregulation of the mTOR pathway. Genetic knockout or AAV9-mediated knockdown of Anxa11 significantly enhanced MYH3+ myofiber maturation, restored S6 phosphorylation, and produced robust functional muscle recovery in mdx mice.","method":"Proteomics, single-nucleus RNA sequencing, genetic knockout, AAV9-mediated knockdown, immunostaining, functional muscle assays in mdx mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function (KO and AAV knockdown) with defined molecular pathway (mTOR/S6) and functional readouts, multiple orthogonal methods","pmids":["42098143"],"is_preprint":false},{"year":2025,"finding":"ANXA11 β-hydroxybutyrylation (Kbhb modification) was detected in high-glucose-treated cardiomyocytes. ANXA11 binds to Cep55, and ANXA11 overexpression increased γ-Tubulin and PLK4 expression (centriole duplication markers) and decreased mitochondrial membrane potential and ATP levels, linking ANXA11 to centriole amplification and mitochondrial dysfunction in diabetic cardiomyopathy.","method":"Co-immunoprecipitation (detection of Kbhb modification and ANXA11-Cep55 binding), western blot, immunofluorescence, mitochondrial membrane potential and ATP assays, in vivo DCM model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP for PTM and binding partner, single lab, limited mechanistic follow-up","pmids":["40865591"],"is_preprint":false},{"year":2024,"finding":"ANXA11 functions as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner. This binding retains miR-148a-3p within the cell, inhibiting its sorting into small extracellular vesicles (sEV). Cisplatin stimulation reduces ANXA11 expression, promoting miR-148a-3p efflux through sEV pathways and contributing to drug resistance in laryngeal squamous cell carcinoma.","method":"RNA pull-down, mass spectrometry, EMSA, immunostaining, microRNA FISH, in vivo xenograft experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down with MS identification, EMSA for direct binding, plus in vivo functional validation, single lab","pmids":["39259536"],"is_preprint":false},{"year":2015,"finding":"ANXA11 knockdown in hepatocarcinoma Hca-P cells promoted migration, invasion, lymph node metastasis, and 5-FU resistance. ANXA11 downregulation increased c-Jun (pSer73) and decreased c-Jun (pSer243) levels, with effects on c-Jun enhanced by combination with 5-FU treatment, indicating ANXA11 regulates lymph node metastasis and 5-FU resistance via the c-Jun pathway.","method":"Stable shRNA knockdown, in vitro migration/invasion assays, in vivo tumor growth and lymph node metastasis assays, western blot for c-Jun phosphorylation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clean stable knockdown with defined in vitro and in vivo phenotypes and signaling readout, single lab","pmids":["26908448"],"is_preprint":false},{"year":2018,"finding":"siRNA silencing of ANXA11 in gastric cancer cell lines (SGC-7901 and AGS) inhibited cell proliferation, colony formation, migration, and invasion through the AKT/GSK-3β pathway.","method":"siRNA knockdown, proliferation assays, migration/invasion assays, western blot for AKT/GSK-3β pathway components","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA) with pathway readout, single lab, no rescue or orthogonal confirmation","pmids":["29306955"],"is_preprint":false},{"year":2024,"finding":"An ANXA11 P93S variant in iPSC-derived neurons led to decreased lysosome colocalization, decreased neuritic RNA, and decreased nuclear TDP-43 with cryptic exon expression, consistent with established ANXA11 functions in lysosomal-RNA granule co-trafficking and TDP-43 regulation.","method":"iPSC-derived neurons, lysosome colocalization imaging, HCR FISH for cryptic exons, single-cell multiomic profiling (neurons and microglia)","journal":"Alzheimer's & dementia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC-derived neuron model with multiple orthogonal readouts including multiomic profiling, single lab","pmids":["38923692"],"is_preprint":false}],"current_model":"ANXA11 is a Ca²⁺-regulated, low-complexity domain-containing protein that functions as a molecular tether linking RNP granules to lysosomes for axonal RNA co-trafficking, where its N-terminus undergoes Ca²⁺-controlled conformational switching and liquid-liquid phase separation regulated by interactors ALG2 and CALC; in neurodegeneration, ANXA11's low-complexity domain co-assembles with TDP-43 to form heteromeric amyloid filaments (as determined by cryo-EM in FTLD-TDP type C brains), ALS-associated mutations disrupt Ca²⁺ homeostasis, stress granule dynamics, protein translation, and cause abnormal phase separation and co-aggregation with TDP-43/FUS, while ANXA11 also participates in plasma membrane repair (upstream of ESCRT-III), regulates muscle regeneration via the mTOR pathway, and acts as a non-canonical RNA-binding protein that retains miR-148a-3p to modulate drug resistance."},"narrative":{"mechanistic_narrative":"ANXA11 is a Ca²⁺-regulated, low-complexity-domain protein that acts as a molecular tether coupling RNP granule condensates to lysosomal membranes for intracellular RNA co-trafficking [PMID:40118863, PMID:36993242]. Its function is governed by a Ca²⁺-controlled conformational switch: in the absence of Ca²⁺ the N-terminal low-complexity domain and the C-terminal annexin core fold into a closed self-interacting state, while Ca²⁺ disrupts this interaction, opening the protein so that both domains can simultaneously engage RNA and lipid membranes [PMID:bio_10.1101_2025.10.27.684738]. Phase-state changes driven by the N-terminal low-complexity domain induce a coupled phase change in the underlying lysosomal lipids, a protein–lipid coupling tuned by the interactors ALG2 and CALC [PMID:40118863, PMID:36993242]. ANXA11 is also recruited acutely to sites of plasma membrane damage during the sealing phase upstream of ESCRT-III/CHMP2B [PMID:bio_10.1101_2024.11.19.624330], retains miR-148a-3p intracellularly to block its sorting into extracellular vesicles [PMID:39259536], and restrains maturation of regenerative myofibers through the mTOR/S6 pathway [PMID:42098143]. ANXA11 mutations cause familial ALS and frontotemporal dementia: N-terminal variants (e.g. p.G38R, p.D40G, p.P36R) enhance aggregation and abnormal phase separation while C-terminal variants (p.H390P, p.R456H) alter Ca²⁺ responses, and all disrupt Ca²⁺ homeostasis and stress granule disassembly, driving cytoplasmic sequestration and co-aggregation with FUS, hnRNPA1, and TDP-43 [PMID:33087501, PMID:36458208]. In FTLD-TDP type C brains a ~22 kDa N-terminal ANXA11 fragment co-assembles with TDP-43 into heteromeric amyloid filaments, with ANXA11 residues L39–Y74 forming a hydrophobic interface with the TDP-43 fold [PMID:39260416, PMID:38979278].","teleology":[{"year":2015,"claim":"Early loss-of-function studies first linked ANXA11 to tumor cell behavior, establishing it as a regulator of migration, invasion, and chemoresistance before its neuronal functions were known.","evidence":"Stable shRNA knockdown in hepatocarcinoma cells with in vitro and in vivo metastasis assays and c-Jun phosphorylation readout","pmids":["26908448"],"confidence":"Medium","gaps":["Direct molecular mechanism connecting ANXA11 to c-Jun phosphorylation not defined","No structural or biophysical basis for the phenotype","Relationship to later-defined RNA/lysosome functions unaddressed"]},{"year":2018,"claim":"A second cancer context reinforced ANXA11's role in proliferation and invasion through a distinct signaling axis.","evidence":"siRNA silencing in gastric cancer cell lines with AKT/GSK-3β pathway western blots","pmids":["29306955"],"confidence":"Low","gaps":["Single method (siRNA) without rescue or orthogonal confirmation","Mechanistic link to AKT/GSK-3β correlative","No in vivo validation"]},{"year":2020,"claim":"Exome sequencing of ALS patients identified ANXA11 variants and established that domain-specific mutations converge on Ca²⁺ homeostasis, stress granule dynamics, and co-aggregation with RNA-binding proteins, defining ANXA11 as an ALS gene.","evidence":"Exome sequencing, Ca²⁺ imaging, phase separation and stress granule assays, Co-IP, and patient brain tissue immunofluorescence in motor neuron models","pmids":["33087501"],"confidence":"High","gaps":["Physiological (non-disease) function of ANXA11 not yet defined","Mechanism by which C-terminal variants alter Ca²⁺ response unresolved","Direct versus indirect basis of FUS/hnRNPA1 interaction not structurally characterized"]},{"year":2022,"claim":"FTD-linked variants in patient-derived cells extended the disease phenotype to include impaired protein translation alongside Ca²⁺ and stress granule defects, bridging ALS and FTD pathophysiology.","evidence":"Calcium imaging, stress granule dynamics, and protein translation assays in patient-derived fibroblasts","pmids":["36458208"],"confidence":"Medium","gaps":["Causal chain from ANXA11 variant to translation defect not established","Single lab, patient fibroblasts only","No neuronal validation in this study"]},{"year":2023,"claim":"Systematic comparison of Asp40 variants showed a shared aggregation-prone pathophysiology and extended ANXA11 proteinopathy to skeletal muscle, broadening the clinical spectrum.","evidence":"Recombinant protein phase separation assays, patient fibroblast stress granule dynamics, and muscle biopsy histopathology with super-resolution imaging","pmids":["36651622"],"confidence":"Medium","gaps":["Why Asp40 substitutions differ in aggregation propensity not mechanistically explained","Relationship between muscle and neuronal aggregates unclear","Single lab"]},{"year":2024,"claim":"Cryo-EM of FTLD-TDP type C patient brain resolved the long-standing question of how ANXA11 contributes to TDP-43 proteinopathy, revealing a heteromeric amyloid filament built from an N-terminal ANXA11 fragment and the TDP-43 low-complexity domain.","evidence":"Cryo-EM structure determination from patient brain tissue with immunoblot and IHC validation","pmids":["39260416","38979278"],"confidence":"High","gaps":["Trigger generating the ~22 kDa N-terminal fragment unknown","Whether the heteromeric filament is causative or downstream of disease not resolved","Role of the annexin core domain in filament formation unaddressed"]},{"year":2024,"claim":"ANXA11 was defined as a non-canonical RNA-binding protein that sequesters a specific microRNA, linking its RNA-binding capacity to extracellular vesicle cargo control and chemoresistance.","evidence":"RNA pull-down with MS, EMSA, microRNA FISH, and in vivo xenografts in laryngeal squamous cell carcinoma","pmids":["39259536"],"confidence":"Medium","gaps":["Domain mediating sequence-specific miR-148a-3p binding not mapped","Generality beyond miR-148a-3p unknown","Connection to lysosomal RNA-trafficking role not examined"]},{"year":2024,"claim":"An iPSC-neuron variant model connected ANXA11 dysfunction mechanistically to reduced lysosome colocalization, loss of neuritic RNA, and TDP-43 nuclear depletion with cryptic exon expression, unifying its trafficking and proteinopathy roles in a human neuronal system.","evidence":"iPSC-derived neurons, lysosome colocalization imaging, HCR FISH for cryptic exons, and single-cell multiomics","pmids":["38923692"],"confidence":"Medium","gaps":["Causal ordering of lysosome, RNA, and TDP-43 defects not resolved","Variant-specific versus general mechanism unclear","Single lab"]},{"year":2025,"claim":"A knock-in mouse demonstrated that an ANXA11 mutation causes late-onset motor neuron disease in vivo, with co-aggregation, autophagic failure, mTORC1 hyperactivation, and neuroinflammation establishing a gain-of-function mechanism.","evidence":"p.P36R knock-in mouse with immunofluorescence, EM, autophagy flux biochemistry, and behavioral assessment","pmids":["39755715"],"confidence":"High","gaps":["Whether autophagic impairment is cause or consequence of aggregation unresolved","Initiating molecular event preceding inclusion formation unknown","Single mouse model/lab"]},{"year":2025,"claim":"Biophysical reconstitution and live-cell work resolved the core physiological mechanism: ANXA11 tethers RNP granules to lysosomes via Ca²⁺-gated conformational switching and N-terminal-driven protein–lipid phase coupling regulated by ALG2 and CALC.","evidence":"Live-cell imaging, nanomechanical biophysics, interaction studies, and in vitro reconstitution with recombinant domain constructs and mutagenesis","pmids":["40118863","36993242","bio_10.1101_2025.10.27.684738"],"confidence":"High","gaps":["How ALG2/CALC mechanically alter the phase state at molecular resolution incomplete","In vivo confirmation of the conformational switch model pending (preprint for the conformational mechanism)","Link between physiological tethering and disease aggregation not fully mapped"]},{"year":2025,"claim":"Independent disease contexts extended ANXA11 function to muscle regeneration and cardiomyocyte biology, showing it restrains regenerative myofiber maturation via mTOR/S6 and links to centriole amplification and mitochondrial dysfunction.","evidence":"Genetic knockout and AAV9 knockdown in mdx mice with proteomics and snRNA-seq; Co-IP of ANXA11–Cep55 and β-hydroxybutyrylation with mitochondrial assays in a diabetic cardiomyopathy model","pmids":["42098143","40865591"],"confidence":"Medium","gaps":["Mechanism connecting ANXA11 to mTOR/S6 regulation undefined","ANXA11–Cep55 interaction rests on single Co-IP without reciprocal validation","Functional significance of β-hydroxybutyrylation not established"]},{"year":null,"claim":"How the physiological Ca²⁺-gated tethering function transitions to pathological N-terminal fragmentation and heteromeric amyloid assembly with TDP-43 remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["Protease/event generating the ~22 kDa N-terminal fragment unknown","Whether disrupted lysosome tethering initiates aggregation or vice versa unresolved","No therapeutic intervention point validated against the conformational/phase mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":[],"partners":["ALG2","CALC","TDP-43","FUS","HNRNPA1","CHMP2B","CEP55"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50995","full_name":"Annexin A11","aliases":["56 kDa autoantigen","Annexin XI","Annexin-11","Calcyclin-associated annexin 50","CAP-50"],"length_aa":505,"mass_kda":54.4,"function":"Binds specifically to calcyclin in a calcium-dependent manner (By similarity). Required for midbody formation and completion of the terminal phase of cytokinesis","subcellular_location":"Cytoplasm; Melanosome; Nucleus envelope; Nucleus, nucleoplasm; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/P50995/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANXA11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000122359","cell_line_id":"CID001094","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"PRDX3","stoichiometry":10.0},{"gene":"OAT","stoichiometry":4.0},{"gene":"CALD1","stoichiometry":0.2},{"gene":"HSPBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001094","total_profiled":1310},"omim":[{"mim_id":"619733","title":"INCLUSION BODY MYOPATHY AND BRAIN WHITE MATTER ABNORMALITIES; IBMWMA","url":"https://www.omim.org/entry/619733"},{"mim_id":"617839","title":"AMYOTROPHIC LATERAL SCLEROSIS 23; ALS23","url":"https://www.omim.org/entry/617839"},{"mim_id":"612388","title":"SARCOIDOSIS, SUSCEPTIBILITY TO, 3; SS3","url":"https://www.omim.org/entry/612388"},{"mim_id":"602572","title":"ANNEXIN A11; ANXA11","url":"https://www.omim.org/entry/602572"},{"mim_id":"602396","title":"ANNEXIN A8; ANXA8","url":"https://www.omim.org/entry/602396"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANXA11"},"hgnc":{"alias_symbol":[],"prev_symbol":["ANX11"]},"alphafold":{"accession":"P50995","domains":[{"cath_id":"1.10.220.10","chopping":"201-258","consensus_level":"high","plddt":97.1429,"start":201,"end":258},{"cath_id":"1.10.220.10","chopping":"346-415_422-428","consensus_level":"medium","plddt":95.9805,"start":346,"end":428},{"cath_id":"1.10.220.10","chopping":"431-505","consensus_level":"medium","plddt":96.9977,"start":431,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50995","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50995-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50995-F1-predicted_aligned_error_v6.png","plddt_mean":75.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANXA11","jax_strain_url":"https://www.jax.org/strain/search?query=ANXA11"},"sequence":{"accession":"P50995","fasta_url":"https://rest.uniprot.org/uniprotkb/P50995.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50995/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50995"}},"corpus_meta":[{"pmid":"19165924","id":"PMC_19165924","title":"Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19165924","citation_count":202,"is_preprint":false},{"pmid":"31088485","id":"PMC_31088485","title":"Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31088485","citation_count":110,"is_preprint":false},{"pmid":"33087501","id":"PMC_33087501","title":"ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics.","date":"2020","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33087501","citation_count":72,"is_preprint":false},{"pmid":"39260416","id":"PMC_39260416","title":"Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39260416","citation_count":68,"is_preprint":false},{"pmid":"23151485","id":"PMC_23151485","title":"Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans.","date":"2012","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23151485","citation_count":53,"is_preprint":false},{"pmid":"29845112","id":"PMC_29845112","title":"ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia.","date":"2018","source":"Neurology. 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The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains, with an extensive hydrophobic interface at the centre. The majority of ANXA11 in these filaments exists as an ~22 kDa N-terminal fragment lacking the annexin core domain.\",\n      \"method\": \"Cryo-electron microscopy structure determination from patient brain tissue, immunoblotting, immunohistochemistry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with atomic-level detail from patient tissue, validated by immunoblot and IHC, peer-reviewed in Nature and independently confirmed by preprint (PMID:38979278)\",\n      \"pmids\": [\"39260416\", \"38979278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. Changes to the protein phase state driven by the low-complexity ANXA11 N-terminus induce a coupled phase-state change in the lipids of the underlying lysosomal membrane. The ANXA11-interacting proteins ALG2 and CALC were identified as potent regulators of this ANXA11-based protein-lipid phase coupling, influencing the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules.\",\n      \"method\": \"Live-cell imaging, biophysical assays (nanomechanics), identification of interacting proteins (ALG2, CALC), co-trafficking experiments, loss-of-function studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biophysics, live imaging, interaction studies), replicated in both preprint and peer-reviewed publication by same group (PMID:36993242, PMID:40118863)\",\n      \"pmids\": [\"40118863\", \"36993242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA11 regulates intracellular Ca2+ homeostasis and stress granule dynamics. ALS-associated N-terminal low-complexity domain variants (p.G38R, p.D40G) enhanced aggregation propensity and underwent abnormal phase separation, while C-terminal ANX domain variants (p.H390P, p.R456H) altered Ca2+ responses. All four variants caused alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. Ca2+-dependent interaction and co-aggregation between ANXA11 and ALS-causative RNA-binding proteins FUS and hnRNPA1 were observed in motor neuron cells and in brain from an ALS-FUS patient. ALS-linked ANXA11 variants caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis.\",\n      \"method\": \"Exome sequencing of ALS patients, Ca2+ imaging, stress granule assays, phase separation assays, Co-immunoprecipitation, immunofluorescence in motor neuron cells and patient brain tissue, apoptosis assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional methods (Ca2+ imaging, phase separation, Co-IP, patient brain tissue validation) in a single rigorous study\",\n      \"pmids\": [\"33087501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ca2+ acts as a master regulator of ANXA11 physiological function by modulating its conformational states. In the absence of Ca2+, the N-terminal (Nt) and C-terminal (Ct) domains interact with each other in a closed state. In the presence of Ca2+, this self-interaction is disrupted (open state), allowing both domains to interact with RNA and liposomes simultaneously. The ALS-associated p.D40G mutation in the Nt domain destabilizes interdomain interactions and bypasses Ca2+ regulation, leading to aberrant aggregation.\",\n      \"method\": \"In vitro biophysical assays with recombinant ANXA11 domain constructs, liposome binding assays, RNA binding assays, conformational analysis, mutagenesis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with mutagenesis, but preprint only, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.27.684738\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a p.P36R knock-in mouse model, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions in motor neurons and cortical neurons from 2 months of age. Autophagic flux was intact at 2 months but impaired by 9 months (decreased Beclin-1 and LC3BII/I, increased SQSTM1/p62, mTORC1 hyperactivation). Significant motor neuron loss and neuroinflammation were detected by 9 months. These findings implicate gain-of-function ANXA11 mutation in late-onset motor neuron disease via proteinopathy, neurodegeneration, neuroinflammation, and autophagic dysfunction.\",\n      \"method\": \"Knock-in mouse model (p.P36R), immunofluorescence, electron microscopy, autophagy flux assays, western blot, behavioral assessment\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in model with multiple orthogonal readouts (EM, biochemistry, behavior, histopathology), single lab\",\n      \"pmids\": [\"39755715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA11 and CHMP2B act sequentially in plasma membrane repair. Annexins (including ANXA11) are recruited immediately to sites of membrane damage (sealing phase), while ESCRT-III assembles only after membrane sealing to shed damaged membranes. FTD- and ALS-associated mutations in ANXA11 compromise the membrane repair process.\",\n      \"method\": \"Live-cell imaging of membrane damage and repair, temporal recruitment assays, loss-of-function with ALS/FTD mutants\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — live imaging with temporal resolution and mutant validation, but preprint only, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.11.19.624330\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA11 variants at Asp40 position (p.D40G, p.D40Y, p.D40Ile) share a common pathophysiology: in vitro studies using recombinant ANXA11 proteins showed abnormal phase separation, with p.D40Ile being more aggregation-prone than p.D40G. Patient fibroblasts with Asp40 variants exhibited defects in stress granule dynamics and clearance. Muscle histopathology showed ANXA11 protein aggregates, with super-resolution imaging revealing distinct aggregate structures in the sarcoplasm.\",\n      \"method\": \"Recombinant protein phase separation assays, patient fibroblast stress granule dynamics, muscle biopsy histopathology, super-resolution imaging\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with recombinant proteins plus patient-derived fibroblast and tissue validation, single lab\",\n      \"pmids\": [\"36651622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Patient fibroblasts carrying FTD-linked ANXA11 variants p.P36R and p.D40G showed impaired intracellular calcium homeostasis, defective stress granule disassembly, and impaired protein translation.\",\n      \"method\": \"Calcium imaging, stress granule dynamics assays, protein translation assays in patient-derived fibroblasts\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts in patient-derived cells, single lab, corroborates prior findings in PMID:33087501\",\n      \"pmids\": [\"36458208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA11 is upregulated in regenerative MYH3+ myofibers in mdx mice and DMD patients and disrupts maturation of regenerative myofibers via dysregulation of the mTOR pathway. Genetic knockout or AAV9-mediated knockdown of Anxa11 significantly enhanced MYH3+ myofiber maturation, restored S6 phosphorylation, and produced robust functional muscle recovery in mdx mice.\",\n      \"method\": \"Proteomics, single-nucleus RNA sequencing, genetic knockout, AAV9-mediated knockdown, immunostaining, functional muscle assays in mdx mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function (KO and AAV knockdown) with defined molecular pathway (mTOR/S6) and functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"42098143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANXA11 β-hydroxybutyrylation (Kbhb modification) was detected in high-glucose-treated cardiomyocytes. ANXA11 binds to Cep55, and ANXA11 overexpression increased γ-Tubulin and PLK4 expression (centriole duplication markers) and decreased mitochondrial membrane potential and ATP levels, linking ANXA11 to centriole amplification and mitochondrial dysfunction in diabetic cardiomyopathy.\",\n      \"method\": \"Co-immunoprecipitation (detection of Kbhb modification and ANXA11-Cep55 binding), western blot, immunofluorescence, mitochondrial membrane potential and ATP assays, in vivo DCM model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for PTM and binding partner, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"40865591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANXA11 functions as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner. This binding retains miR-148a-3p within the cell, inhibiting its sorting into small extracellular vesicles (sEV). Cisplatin stimulation reduces ANXA11 expression, promoting miR-148a-3p efflux through sEV pathways and contributing to drug resistance in laryngeal squamous cell carcinoma.\",\n      \"method\": \"RNA pull-down, mass spectrometry, EMSA, immunostaining, microRNA FISH, in vivo xenograft experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down with MS identification, EMSA for direct binding, plus in vivo functional validation, single lab\",\n      \"pmids\": [\"39259536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANXA11 knockdown in hepatocarcinoma Hca-P cells promoted migration, invasion, lymph node metastasis, and 5-FU resistance. ANXA11 downregulation increased c-Jun (pSer73) and decreased c-Jun (pSer243) levels, with effects on c-Jun enhanced by combination with 5-FU treatment, indicating ANXA11 regulates lymph node metastasis and 5-FU resistance via the c-Jun pathway.\",\n      \"method\": \"Stable shRNA knockdown, in vitro migration/invasion assays, in vivo tumor growth and lymph node metastasis assays, western blot for c-Jun phosphorylation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clean stable knockdown with defined in vitro and in vivo phenotypes and signaling readout, single lab\",\n      \"pmids\": [\"26908448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA silencing of ANXA11 in gastric cancer cell lines (SGC-7901 and AGS) inhibited cell proliferation, colony formation, migration, and invasion through the AKT/GSK-3β pathway.\",\n      \"method\": \"siRNA knockdown, proliferation assays, migration/invasion assays, western blot for AKT/GSK-3β pathway components\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA) with pathway readout, single lab, no rescue or orthogonal confirmation\",\n      \"pmids\": [\"29306955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An ANXA11 P93S variant in iPSC-derived neurons led to decreased lysosome colocalization, decreased neuritic RNA, and decreased nuclear TDP-43 with cryptic exon expression, consistent with established ANXA11 functions in lysosomal-RNA granule co-trafficking and TDP-43 regulation.\",\n      \"method\": \"iPSC-derived neurons, lysosome colocalization imaging, HCR FISH for cryptic exons, single-cell multiomic profiling (neurons and microglia)\",\n      \"journal\": \"Alzheimer's & dementia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC-derived neuron model with multiple orthogonal readouts including multiomic profiling, single lab\",\n      \"pmids\": [\"38923692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANXA11 is a Ca²⁺-regulated, low-complexity domain-containing protein that functions as a molecular tether linking RNP granules to lysosomes for axonal RNA co-trafficking, where its N-terminus undergoes Ca²⁺-controlled conformational switching and liquid-liquid phase separation regulated by interactors ALG2 and CALC; in neurodegeneration, ANXA11's low-complexity domain co-assembles with TDP-43 to form heteromeric amyloid filaments (as determined by cryo-EM in FTLD-TDP type C brains), ALS-associated mutations disrupt Ca²⁺ homeostasis, stress granule dynamics, protein translation, and cause abnormal phase separation and co-aggregation with TDP-43/FUS, while ANXA11 also participates in plasma membrane repair (upstream of ESCRT-III), regulates muscle regeneration via the mTOR pathway, and acts as a non-canonical RNA-binding protein that retains miR-148a-3p to modulate drug resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANXA11 is a Ca²⁺-regulated, low-complexity-domain protein that acts as a molecular tether coupling RNP granule condensates to lysosomal membranes for intracellular RNA co-trafficking [#1]. Its function is governed by a Ca²⁺-controlled conformational switch: in the absence of Ca²⁺ the N-terminal low-complexity domain and the C-terminal annexin core fold into a closed self-interacting state, while Ca²⁺ disrupts this interaction, opening the protein so that both domains can simultaneously engage RNA and lipid membranes [#3]. Phase-state changes driven by the N-terminal low-complexity domain induce a coupled phase change in the underlying lysosomal lipids, a protein–lipid coupling tuned by the interactors ALG2 and CALC [#1]. ANXA11 is also recruited acutely to sites of plasma membrane damage during the sealing phase upstream of ESCRT-III/CHMP2B [#5], retains miR-148a-3p intracellularly to block its sorting into extracellular vesicles [#10], and restrains maturation of regenerative myofibers through the mTOR/S6 pathway [#8]. ANXA11 mutations cause familial ALS and frontotemporal dementia: N-terminal variants (e.g. p.G38R, p.D40G, p.P36R) enhance aggregation and abnormal phase separation while C-terminal variants (p.H390P, p.R456H) alter Ca²⁺ responses, and all disrupt Ca²⁺ homeostasis and stress granule disassembly, driving cytoplasmic sequestration and co-aggregation with FUS, hnRNPA1, and TDP-43 [#2, #7]. In FTLD-TDP type C brains a ~22 kDa N-terminal ANXA11 fragment co-assembles with TDP-43 into heteromeric amyloid filaments, with ANXA11 residues L39–Y74 forming a hydrophobic interface with the TDP-43 fold [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Early loss-of-function studies first linked ANXA11 to tumor cell behavior, establishing it as a regulator of migration, invasion, and chemoresistance before its neuronal functions were known.\",\n      \"evidence\": \"Stable shRNA knockdown in hepatocarcinoma cells with in vitro and in vivo metastasis assays and c-Jun phosphorylation readout\",\n      \"pmids\": [\"26908448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism connecting ANXA11 to c-Jun phosphorylation not defined\", \"No structural or biophysical basis for the phenotype\", \"Relationship to later-defined RNA/lysosome functions unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A second cancer context reinforced ANXA11's role in proliferation and invasion through a distinct signaling axis.\",\n      \"evidence\": \"siRNA silencing in gastric cancer cell lines with AKT/GSK-3β pathway western blots\",\n      \"pmids\": [\"29306955\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (siRNA) without rescue or orthogonal confirmation\", \"Mechanistic link to AKT/GSK-3β correlative\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Exome sequencing of ALS patients identified ANXA11 variants and established that domain-specific mutations converge on Ca²⁺ homeostasis, stress granule dynamics, and co-aggregation with RNA-binding proteins, defining ANXA11 as an ALS gene.\",\n      \"evidence\": \"Exome sequencing, Ca²⁺ imaging, phase separation and stress granule assays, Co-IP, and patient brain tissue immunofluorescence in motor neuron models\",\n      \"pmids\": [\"33087501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological (non-disease) function of ANXA11 not yet defined\", \"Mechanism by which C-terminal variants alter Ca²⁺ response unresolved\", \"Direct versus indirect basis of FUS/hnRNPA1 interaction not structurally characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"FTD-linked variants in patient-derived cells extended the disease phenotype to include impaired protein translation alongside Ca²⁺ and stress granule defects, bridging ALS and FTD pathophysiology.\",\n      \"evidence\": \"Calcium imaging, stress granule dynamics, and protein translation assays in patient-derived fibroblasts\",\n      \"pmids\": [\"36458208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from ANXA11 variant to translation defect not established\", \"Single lab, patient fibroblasts only\", \"No neuronal validation in this study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Systematic comparison of Asp40 variants showed a shared aggregation-prone pathophysiology and extended ANXA11 proteinopathy to skeletal muscle, broadening the clinical spectrum.\",\n      \"evidence\": \"Recombinant protein phase separation assays, patient fibroblast stress granule dynamics, and muscle biopsy histopathology with super-resolution imaging\",\n      \"pmids\": [\"36651622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why Asp40 substitutions differ in aggregation propensity not mechanistically explained\", \"Relationship between muscle and neuronal aggregates unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM of FTLD-TDP type C patient brain resolved the long-standing question of how ANXA11 contributes to TDP-43 proteinopathy, revealing a heteromeric amyloid filament built from an N-terminal ANXA11 fragment and the TDP-43 low-complexity domain.\",\n      \"evidence\": \"Cryo-EM structure determination from patient brain tissue with immunoblot and IHC validation\",\n      \"pmids\": [\"39260416\", \"38979278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger generating the ~22 kDa N-terminal fragment unknown\", \"Whether the heteromeric filament is causative or downstream of disease not resolved\", \"Role of the annexin core domain in filament formation unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ANXA11 was defined as a non-canonical RNA-binding protein that sequesters a specific microRNA, linking its RNA-binding capacity to extracellular vesicle cargo control and chemoresistance.\",\n      \"evidence\": \"RNA pull-down with MS, EMSA, microRNA FISH, and in vivo xenografts in laryngeal squamous cell carcinoma\",\n      \"pmids\": [\"39259536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain mediating sequence-specific miR-148a-3p binding not mapped\", \"Generality beyond miR-148a-3p unknown\", \"Connection to lysosomal RNA-trafficking role not examined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An iPSC-neuron variant model connected ANXA11 dysfunction mechanistically to reduced lysosome colocalization, loss of neuritic RNA, and TDP-43 nuclear depletion with cryptic exon expression, unifying its trafficking and proteinopathy roles in a human neuronal system.\",\n      \"evidence\": \"iPSC-derived neurons, lysosome colocalization imaging, HCR FISH for cryptic exons, and single-cell multiomics\",\n      \"pmids\": [\"38923692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of lysosome, RNA, and TDP-43 defects not resolved\", \"Variant-specific versus general mechanism unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A knock-in mouse demonstrated that an ANXA11 mutation causes late-onset motor neuron disease in vivo, with co-aggregation, autophagic failure, mTORC1 hyperactivation, and neuroinflammation establishing a gain-of-function mechanism.\",\n      \"evidence\": \"p.P36R knock-in mouse with immunofluorescence, EM, autophagy flux biochemistry, and behavioral assessment\",\n      \"pmids\": [\"39755715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagic impairment is cause or consequence of aggregation unresolved\", \"Initiating molecular event preceding inclusion formation unknown\", \"Single mouse model/lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Biophysical reconstitution and live-cell work resolved the core physiological mechanism: ANXA11 tethers RNP granules to lysosomes via Ca²⁺-gated conformational switching and N-terminal-driven protein–lipid phase coupling regulated by ALG2 and CALC.\",\n      \"evidence\": \"Live-cell imaging, nanomechanical biophysics, interaction studies, and in vitro reconstitution with recombinant domain constructs and mutagenesis\",\n      \"pmids\": [\"40118863\", \"36993242\", \"bio_10.1101_2025.10.27.684738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ALG2/CALC mechanically alter the phase state at molecular resolution incomplete\", \"In vivo confirmation of the conformational switch model pending (preprint for the conformational mechanism)\", \"Link between physiological tethering and disease aggregation not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Independent disease contexts extended ANXA11 function to muscle regeneration and cardiomyocyte biology, showing it restrains regenerative myofiber maturation via mTOR/S6 and links to centriole amplification and mitochondrial dysfunction.\",\n      \"evidence\": \"Genetic knockout and AAV9 knockdown in mdx mice with proteomics and snRNA-seq; Co-IP of ANXA11–Cep55 and β-hydroxybutyrylation with mitochondrial assays in a diabetic cardiomyopathy model\",\n      \"pmids\": [\"42098143\", \"40865591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ANXA11 to mTOR/S6 regulation undefined\", \"ANXA11–Cep55 interaction rests on single Co-IP without reciprocal validation\", \"Functional significance of β-hydroxybutyrylation not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the physiological Ca²⁺-gated tethering function transitions to pathological N-terminal fragmentation and heteromeric amyloid assembly with TDP-43 remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease/event generating the ~22 kDa N-terminal fragment unknown\", \"Whether disrupted lysosome tethering initiates aggregation or vice versa unresolved\", \"No therapeutic intervention point validated against the conformational/phase mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ALG2\", \"CALC\", \"TDP-43\", \"FUS\", \"hnRNPA1\", \"CHMP2B\", \"Cep55\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}