ANXA11

ANXA11 is a Ca²⁺-dependent phospholipid-binding protein that tethers ribonucleoprotein (RNP) granules to lysosomal membranes for co-trafficking, couples RNA binding and membrane association through a conformational switch between a closed auto-inhibited state and an open Ca²⁺-activated state, and participates in plasma membrane repair (PMID:40118863, PMID:33087501). The low-complexity N-terminal domain drives liquid–liquid phase separation, binds RNA (including specific microRNAs such as miR-148a-3p), and mediates interactions with stress granule components FUS and hnRNPA1, while the C-terminal annexin core domain confers Ca²⁺-regulated liposome and membrane binding (PMID:33087501, PMID:39259536, PMID:40118863). ALS- and FTD-associated mutations in the N-terminal domain (e.g., G38R, D40G, P36R) enhance aggregation propensity, bypass Ca²⁺ regulation, impair stress granule disassembly and calcium homeostasis, cause TDP-43 mislocalization and co-aggregation, and progressively disrupt autophagy in vivo (PMID:33087501, PMID:39755715, PMID:38923692). In FTLD-TDP type C, the ANXA11 N-terminal low-complexity domain co-assembles with TDP-43 into heteromeric amyloid filaments resolved at atomic resolution by cryo-EM (PMID:39260416).

1. 1998 Medium

   Establishing the genomic position and evolutionary origin of ANXA11 provided the foundation for subsequent functional studies by mapping the gene to 10q22.3-q23.1 and identifying it as a candidate progenitor of multiple human annexins.

   Evidence Fluorescence in situ hybridization and phylogenetic analysis

   PMID:9503022

   Open questions at the time

   • No functional data at this stage
   • Evolutionary relationship to other annexins based on sequence alone
2. 2016 Medium

   Loss-of-function studies first placed ANXA11 in cellular signaling pathways by showing that its depletion promoted migration, invasion, and chemoresistance through altered c-Jun phosphorylation, suggesting a tumor-suppressive role.

   Evidence shRNA knockdown in hepatocarcinoma cells with in vivo metastasis assays and c-Jun phosphorylation readouts

   PMID:26908448

   Open questions at the time

   • Direct biochemical link between ANXA11 and c-Jun kinase/phosphatase not established
   • Single cancer cell line
   • Not replicated independently
3. 2020 High

   A key advance was demonstrating that ALS-associated mutations in the N-terminal low-complexity domain enhanced aggregation and aberrant phase separation, while C-terminal variants altered Ca²⁺ responses, unifying calcium homeostasis, stress granule dynamics, and neurodegeneration under a single ANXA11 mechanism.

   Evidence Exome sequencing, calcium imaging, phase separation and stress granule assays, Co-IP in motor neuron cells and patient brain tissue

   PMID:33087501

   Open questions at the time

   • Structural basis of Ca²⁺-dependent conformational change unknown
   • Whether stress granule defects are cause or consequence of neurodegeneration unclear
4. 2022 Medium

   Patient-derived fibroblasts carrying P36R and D40G mutations validated that impaired calcium homeostasis, defective stress granule disassembly, and impaired protein translation are cell-autonomous consequences of these variants.

   Evidence Patient fibroblast calcium imaging, stress granule dynamics, and translation assays

   PMID:36458208

   Open questions at the time

   • Fibroblasts rather than neurons used
   • Translation impairment mechanism not defined at molecular level
5. 2023 Medium

   Biochemical reconstitution showed that the D40I variant is even more aggregation-prone than D40G, establishing a graded spectrum of phase separation defects at the Asp40 position and confirming stress granule dysfunction in patient tissue.

   Evidence Recombinant protein phase separation assays, patient fibroblast stress granule assays, muscle biopsy histopathology

   PMID:36651622

   Open questions at the time

   • Quantitative relationship between aggregation propensity and disease severity not established
   • Single lab study
6. 2024 High

   The landmark discovery that ANXA11 and TDP-43 co-assemble into heteromeric amyloid filaments in FTLD-TDP type C brains, with an extensive hydrophobic interface between their low-complexity domains, fundamentally redefined the pathological role of ANXA11 from a bystander to a structural co-component of disease-defining inclusions.

   Evidence Cryo-EM of patient brain-derived filaments at atomic resolution, immunoblotting, immunohistochemistry

   PMID:39260416

   Open questions at the time

   • Whether heteromeric filaments form in ALS as well as FTLD-TDP type C is unknown
   • Mechanism of N-terminal cleavage generating the ~22 kDa fragment is unidentified
   • Whether co-assembly is required for toxicity or is an end-stage phenomenon unclear
7. 2024 Medium

   ANXA11 was established as a non-canonical RNA-binding protein that binds miR-148a-3p in a sequence-specific manner, with its intracellular retention of miRNA modulating extracellular vesicle-mediated chemoresistance signaling.

   Evidence RNA pull-down, mass spectrometry, EMSA, microRNA FISH, in vivo xenograft

   PMID:39259536

   Open questions at the time

   • RNA-binding specificity determinants in ANXA11 not mapped
   • Generality of miRNA regulation beyond miR-148a-3p unknown
8. 2024 Medium

   iPSC-derived neuron studies with the P93S variant demonstrated that ANXA11 mutations decrease lysosome–RNA granule co-localization, reduce neuritic RNA, and cause nuclear TDP-43 loss with cryptic exon expression, directly linking the tethering function to TDP-43 nuclear biology.

   Evidence iPSC-derived neurons, immunofluorescence, HCR FISH for cryptic exons

   PMID:38923692

   Open questions at the time

   • Causal chain from lysosome–RNA granule uncoupling to TDP-43 nuclear loss not mechanistically resolved
   • Single mutation studied
9. 2025 High

   The P36R knock-in mouse model provided the first in vivo demonstration that mutant ANXA11 causes progressive TDP-43 and p62-positive co-aggregation, autophagy impairment via mTORC1 hyperactivation, motor neuron loss, and neuroinflammation, establishing a gain-of-function disease mechanism.

   Evidence Knock-in mouse model with longitudinal analysis at 2 and 9 months, electron microscopy, autophagic flux assays

   PMID:39755715

   Open questions at the time

   • How ANXA11 aggregates impair autophagy and activate mTORC1 at the molecular level is undefined
   • Whether motor phenotype fully recapitulates ALS not assessed
10. 2025 High

    The physiological tethering function was mechanistically elaborated: ANXA11's N-terminal phase separation induces coupled phase state changes in lysosomal membrane lipids, and the interacting proteins ALG2 and CALC regulate this phase coupling and the nanomechanical properties of the ANXA11–lysosome ensemble.

    Evidence Live-cell imaging, Co-IP, biophysical membrane nanomechanics assays, phase separation assays

    PMID:40118863

    Open questions at the time

    • Structural details of ALG2/CALC regulation of ANXA11 phase coupling not resolved
    • How membrane lipid phase changes influence RNP granule engagement is not fully defined

• Key unresolved questions include the structural basis of full-length ANXA11's Ca²⁺-dependent conformational switch at atomic resolution, the protease responsible for generating the ~22 kDa N-terminal fragment found in FTLD filaments, and whether ANXA11–TDP-43 heteromeric amyloid formation is a cause or consequence of neurodegeneration.
• No high-resolution structure of full-length ANXA11 in either conformational state
• Identity of the protease generating the pathological N-terminal fragment is unknown
• Causal versus consequential role of heteromeric amyloid filaments in disease not tested