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Physiological and pathological roles of ANXA11: a multifunctional regulator in neurodegeneration and other disorders

Year: 2026

Type: article

Abstract: Annexin A11 (ANXA11) is a Ca²⁺-dependent phospholipid-binding protein of the annexin family, which has been traditionally studied for its established roles in tumor progression and autoimmune disorders. Recent studies have highlighted the roles of ANXA11 in newly discovered mechanisms related to neurodegenerative diseases, including liquid-liquid phase separation (LLPS), membrane lipid coupling, and function as a molecular tether linking membraneless organelles to lysosomal membranes. Recent landmark findings reveal that ANXA11 co-assembles with TAR DNA-binding protein 43(TDP-43) into heteromeric amyloid filaments, suggesting that these pathological amyloid structures may play a crucial role in neurodegeneration. In this review, we comprehensively explored the physiological and pathological roles of ANXA11 in neurodegeneration and other disorders, with a focus on LLPS, membrane dynamics, and amyloidogenesis. We discussed potential therapeutic strategies targeting the unique properties of ANXA11 and proposed several critical scientific questions that need to be explored. 1. We summarized the membrane-associated role of ANXA11 in tethering membraneless RNA granules to lysosomes, revealing its interference with axonal RNA transport and its implications for neurodegenerative disease pathogenesis. 2. We highlighted the discovery of ANXA11-TDP-43 heteromeric amyloid filaments, as a novel pathological aggregation in protein-misfolding disorders. 3. We briefly introduced the role of ANXA11 as a disease-specific autoantigen in certain autoimmune diseases and its involvement in cancer metastasis, invasion, and therapy resistance. 4. We explored potential therapeutic strategies targeting ANXA11 and outlined critical scientific questions that require further exploration. ANXA11 in Health and Disease: Membrane-Associated Roles and Beyond. In neurodegenerative diseases, ANXA11 mutations may drive protein aggregation and they together induce multifaceted cellular dysfunction, including dysregulated stress granules dynamics, sustained neuroinflammation, compromised nuclear envelope integrity (e.g.,lamin B2 mislocalization), disrupted Ca²⁺ homeostasis, impaired RNA granule transport, and defective autophagic flux. In cancers, ANXA11 promotes tumorigenesis, regulates cancer metastasis/invasion and mediates drug resistance, serving as a potential diagnostic biomarker. Anti-ANXA11 autoantibodies are associated with multiple autoimmune diseases.

Source: Cell Communication and Signaling

DOI: 10.1186/s12964-025-02629-7