ANXA11

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).

1. 2015 Medium

   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

   PMID:26908448

   Open questions at the time

   • 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
2. 2018 Low

   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

   PMID:29306955

   Open questions at the time

   • Single method (siRNA) without rescue or orthogonal confirmation
   • Mechanistic link to AKT/GSK-3β correlative
   • No in vivo validation
3. 2020 High

   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

   PMID:33087501

   Open questions at the time

   • 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
4. 2022 Medium

   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

   PMID:36458208

   Open questions at the time

   • Causal chain from ANXA11 variant to translation defect not established
   • Single lab, patient fibroblasts only
   • No neuronal validation in this study
5. 2023 Medium

   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

   PMID:36651622

   Open questions at the time

   • Why Asp40 substitutions differ in aggregation propensity not mechanistically explained
   • Relationship between muscle and neuronal aggregates unclear
   • Single lab
6. 2024 High

   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

   PMID:38979278 PMID:39260416

   Open questions at the time

   • 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
7. 2024 Medium

   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

   PMID:39259536

   Open questions at the time

   • Domain mediating sequence-specific miR-148a-3p binding not mapped
   • Generality beyond miR-148a-3p unknown
   • Connection to lysosomal RNA-trafficking role not examined
8. 2024 Medium

   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

   PMID:38923692

   Open questions at the time

   • Causal ordering of lysosome, RNA, and TDP-43 defects not resolved
   • Variant-specific versus general mechanism unclear
   • Single lab
9. 2025 High

   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

   PMID:39755715

   Open questions at the time

   • Whether autophagic impairment is cause or consequence of aggregation unresolved
   • Initiating molecular event preceding inclusion formation unknown
   • Single mouse model/lab
10. 2025 High

    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

    PMID:36993242 PMID:40118863 PMID:bio_10.1101_2025.10.27.684738

    Open questions at the time

    • 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
11. 2025 Medium

    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

    PMID:40865591 PMID:42098143

    Open questions at the time

    • 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

• 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.
• 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