NEU1

NEU1 is a sialidase that removes sialic acid residues from glycoproteins and glycolipids in lysosomes and at the cell surface, functioning as a broad regulator of glycoprotein sialylation status with consequences for receptor signaling, innate immunity, cell adhesion, and lysosomal homeostasis. In lysosomes, NEU1 requires chaperoning by protective protein/cathepsin A (PPCA), which prevents NEU1 self-oligomerization and induces a conformational change in its catalytic loop to activate the enzyme (PMID:19666471, PMID:37205763); loss-of-function mutations in NEU1 cause sialidosis, a lysosomal storage disease (PMID:14517945, PMID:25600812). At the cell surface, NEU1 forms constitutive or stimulus-induced complexes with TLR2/3/4, Trk receptors, integrins, and MUC1, and its desialylation of these targets controls receptor dimerization, downstream kinase cascades (NF-κB, FAK/ERK, Akt, MAPK), and inflammatory or metastatic outcomes (PMID:20864924, PMID:20347965, PMID:19151752, PMID:25963144, PMID:31649671). NEU1 deficiency leads to oversialylation of APP and excessive lysosomal exocytosis causing extracellular Aβ release, while activated microglia secrete NEU1 to desialylate phagocytic receptors Trem2 and MerTK, enhancing phagocytosis but also sensitizing neurons to excitotoxicity (PMID:24225533, PMID:35693885).

1. 2003 High

   Establishing that loss-of-function mutations throughout NEU1 cause sialidosis by disrupting enzymatic activity, stability, and lysosomal targeting answered the long-standing question of genotype-phenotype relationships in this lysosomal storage disease.

   Evidence Expression of patient-derived NEU1 mutants with activity assays, immunolocalization, and structural modeling

   PMID:14517945

   Open questions at the time

   • Structural model was homology-based; no experimentally determined NEU1 structure at this time
   • Mechanism by which individual mutations disrupt folding versus catalysis not fully delineated
2. 2009 High

   Demonstrating that PPCA chaperones NEU1 as a heterodimer and prevents its self-oligomerization resolved how NEU1 is maintained in an active, monomeric state in lysosomes.

   Evidence Hydrodynamic analysis, mutagenesis of binding interfaces, and structural modeling of NEU1 oligomers versus PPCA–NEU1 heterodimer

   PMID:19666471

   Open questions at the time

   • The activation mechanism of NEU1 by PPCA was not structurally resolved at atomic level
   • Whether PPCA chaperoning is also required for cell-surface NEU1 pools was unclear
3. 2009 High

   Showing that NEU1 desialylates integrin β4 to attenuate FAK/ERK signaling and suppress colon cancer liver metastasis established NEU1 as a cell-surface signaling modulator with tumor-suppressive function.

   Evidence NEU1 overexpression/silencing in HT-29 cells with lectin blotting of integrin β4 immunoprecipitates, phosphorylation assays, and in vivo metastasis model

   PMID:19151752

   Open questions at the time

   • Whether NEU1 desialylates other integrins with similar signaling consequences was untested
   • The sialic acid linkage specificity on integrin β4 was not defined
4. 2010 Medium

   Discovering that NEU1 is constitutively associated with TLR2/3/4 and that ligand-induced NEU1 activation removes sialyl α-2,3-linked residues to enable TLR4 dimerization and MyD88-dependent NF-κB signaling established NEU1 as a gatekeeper of innate immune receptor activation.

   Evidence Co-immunoprecipitation of NEU1 with TLRs; live-cell sialidase assays; pharmacological inhibition with functional NF-κB readouts

   PMID:20864924

   Open questions at the time

   • Single-lab finding at this stage; the steric hindrance model for TLR dimerization lacked direct structural support
   • Whether NEU1 also regulates TRIF-dependent TLR4 signaling was unknown
5. 2010 High

   Identification of a cell-surface NEU1–MMP-9–TrkA complex in which NGF triggers Gαi-mediated MMP-9 activation and subsequent NEU1 sialidase activity, required for Trk receptor activation and neurite outgrowth, revealed a neurotrophin signaling module dependent on desialylation.

   Evidence Co-immunoprecipitation; live-cell sialidase assays with IC50 determination of Tamiflu; neurite outgrowth in TrkA-PC12 cells and primary neurons

   PMID:20347965

   Open questions at the time

   • The precise sialylated residues on TrkA targeted by NEU1 were not identified
   • Whether this mechanism extends to TrkB/TrkC was not tested
6. 2013 High

   Demonstrating that NEU1 deficiency causes oversialylation and lysosomal accumulation of APP, leading to amyloidogenic processing and Aβ secretion via lysosomal exocytosis, connected sialidase biology to Alzheimer's disease pathology.

   Evidence NEU1-deficient mouse model; APP sialylation and processing assays; lysosomal exocytosis measurements; rescue by cerebral NEU1 injection in AD mouse

   PMID:24225533

   Open questions at the time

   • Whether NEU1 directly desialylates APP or acts on trafficking machinery was not fully resolved
   • Relevance to human sporadic AD beyond the mouse model was not established
7. 2013 High

   Showing that elastin-derived peptides signal through the NEU1-containing elastin receptor complex to activate PI3Kγ in monocytes and drive atherosclerosis, with genetic ablation of cathepsin A–NEU1 in hematopoietic cells abolishing plaque progression, positioned NEU1 as a driver of vascular inflammation.

   Evidence Atherosclerosis mouse models with bone marrow transplant; PI3Kγ KO epistasis; in vitro monocyte ROS and migration assays with neuraminidase inhibition

   PMID:24357053

   Open questions at the time

   • Whether NEU1 sialidase activity per se or its scaffolding role in the elastin receptor complex is the essential function was not distinguished
8. 2015 High

   Revealing that NEU1 desialylates MUC1 ectodomain upon flagellin stimulation, increasing bacterial adhesion but also promoting MUC1-ED shedding as a decoy receptor, uncovered a dual role for NEU1 in airway innate defense.

   Evidence Co-immunoprecipitation of NEU1 with MUC1; Scatchard binding analysis; adhesion/invasion assays; bronchoalveolar lavage from patients

   PMID:25963144

   Open questions at the time

   • The net in vivo benefit versus cost of NEU1-mediated MUC1 desialylation in infection outcome was not resolved
   • Whether NEU1 targets other mucins similarly was not tested
9. 2018 High

   Demonstrating that NEU1 expression is induced by IL-1β/LPS and in turn promotes TNF-α and IL-1β production, forming a positive feedback loop for M1 macrophage polarization, extended NEU1's role from a signal enabler to a transcriptional amplifier of inflammation.

   Evidence CRISPR/Cas9 KO, siRNA, and lentiviral overexpression of NEU1 in primary human CD14+ monocytes and cell lines with cytokine readouts

   PMID:29371126

   Open questions at the time

   • The transcription factors mediating NEU1 induction by IL-1β were not identified
   • Whether this feedback loop operates in vivo during chronic inflammation was not shown
10. 2020 High

    Showing that NEU1 disrupts fibronectin–integrin α5β1 interaction and suppresses Akt signaling to inhibit bladder cancer proliferation and promote apoptosis broadened the integrin-based tumor-suppressive mechanism to additional integrin family members.

    Evidence NEU1 overexpression and siRNA knockdown; co-immunoprecipitation of fibronectin–integrin α5β1; in vivo xenograft in nude mice

    PMID:32164705

    Open questions at the time

    • Whether NEU1 directly desialylates integrin α5, β1, or fibronectin was not distinguished
    • The specific sialylated glycan sites were not mapped
11. 2021 Medium

    Identifying that NEU1 and siglec-E reciprocally regulate TLR4 sialylation — NEU1 promoting MyD88-dependent and siglec-E promoting TRIF-dependent signaling — and that NEU1 prevents Triad3A-mediated TLR4 ubiquitination and degradation, established a sialylation-based toggle between two branches of TLR4 signaling.

    Evidence NEU1 overexpression and siglec-E silencing; co-IP; phosphorylation and ubiquitination assays; cytokine and IFN-β measurements

    PMID:33763070

    Open questions at the time

    • Single-lab study; reciprocal regulation model not validated in vivo
    • Direct evidence that sialylation state of TLR4 determines MyD88 vs. TRIF pathway choice at endogenous expression levels is lacking
12. 2022 High

    Discovering that activated microglia release NEU1 via lysosomal exocytosis and that extracellular NEU1 desialylates Trem2 and MerTK to enhance phagocytosis while also sensitizing neurons to excitotoxicity revealed a paracrine mode of NEU1 action in neuroinflammation.

    Evidence NEU1 knockdown in microglia; lysosomal exocytosis inhibitors; receptor desialylation assays; phagocytosis assays; neuron co-culture experiments

    PMID:35693885

    Open questions at the time

    • Whether extracellular NEU1 is enzymatically active as a monomer or requires PPCA in the extracellular space was not addressed
    • In vivo relevance of paracrine NEU1 in neurodegeneration remains untested
13. 2023 High

    Solving the cryo-EM/X-ray structure of NEU1 revealed two self-association interfaces, a wide substrate-binding cavity, and an inactive catalytic loop conformation, establishing the structural basis for PPCA-induced activation.

    Evidence Crystal and cryo-EM structure determination of murine NEU1; comparison with PPCA-bound complex

    PMID:37205763

    Open questions at the time

    • Structure of the PPCA–NEU1 complex at atomic resolution has not been determined
    • The structural basis for NEU1's substrate selectivity (e.g., α-2,3 vs. α-2,6 sialic acid linkages) is not fully explained

• Key unresolved questions include how NEU1 is trafficked to and retained at the cell surface, whether PPCA is required for cell-surface NEU1 activity, and what determines NEU1's substrate selectivity among different sialylated receptors in vivo.
• No structure of the PPCA–NEU1 complex at atomic resolution
• Mechanism of NEU1 trafficking to cell surface unknown
• In vivo substrate hierarchy for cell-surface NEU1 not established