LGI3

LGI3 is a secreted leucine-rich repeat protein that functions as an extracellular ligand organizing ion channel complexes and, in non-neural contexts, as a survival- and differentiation-promoting signaling factor. In the nervous system, LGI3 is secreted by oligodendrocytes and enriched at juxtaparanodes of myelinated axons, where it binds axonal ADAM23 to control the accumulation and stability of Kv1 channel complexes; loss of LGI3 or ADAM23 disrupts juxtaparanodal Kv1 clustering, alters the axonal refractory period and burst firing, and suppresses Kv1-mediated short-term synaptic plasticity, and a disease-associated LGI3 missense variant is defective in secretion (PMID:36828548, PMID:38194969). In the heart, LGI3 associates with KV1.5 channels in atrial tissue, interferes with the KV1.5/KVβ association, reverses KVβ-induced inactivation, and reduces IKur and KV1.5 surface expression (PMID:41854369). In keratinocytes, LGI3 secretion is driven by UVB and by LPS through a TRIF-dependent NF-κB pathway that binds the LGI3 promoter, and the secreted protein engages ADAM22 and selectively activates the PI3K–Akt axis to promote survival (via MDM2 phosphorylation and p53 degradation), differentiation, and high-glucose migration (via β-catenin accumulation) (PMID:22741557, PMID:31627033, PMID:30091803, PMID:35751164). LGI3 also interacts with and stabilizes flotillin-1, regulating APP trafficking and exosome biogenesis (PMID:20461023). In TFE3-rearranged renal cell carcinoma, LGI3 is a direct transcriptional target of the TFE3 fusion and stabilizes GEMIN6 by blocking its ubiquitination, elevating AURKB to drive tumor progression (PMID:40849584).

1. 2007 Low

   Initial work asked where LGI3 acts and what it associates with in brain, establishing a membrane/endocytic localization and a link to amyloid-β handling that framed later trafficking studies.

   Evidence Immunohistochemistry, subcellular fractionation, and Western blot in aged monkey brain plus Aβ-treated rat astrocyte cultures

   PMID:17387609 PMID:17786549

   Open questions at the time

   • Purely descriptive colocalization without functional manipulation of LGI3
   • No receptor or binding partner identified
   • Proteolytic cleavage inferred from Western blot only
2. 2010 Medium

   To define a molecular partner, LGI3 was shown to bind and reciprocally stabilize flotillin-1, connecting LGI3 to clathrin-dependent endocytosis, APP trafficking, and exosome biogenesis.

   Evidence Co-immunoprecipitation and RNAi knockdown with APP trafficking assays in neural cells

   PMID:20461023

   Open questions at the time

   • No in vitro reconstitution of the LGI3–flotillin-1 complex
   • Single lab
   • Direct vs. indirect binding not resolved
3. 2012 Medium

   Outside the nervous system, LGI3 was identified as a stress-induced secreted survival factor in keratinocytes, linking it to the PI3K–Akt–MDM2–p53 axis.

   Evidence ELISA secretion assay, viability assay, and Western blot for pAkt/pMDM2/p53 in UVB-irradiated HaCaT cells

   PMID:22741557

   Open questions at the time

   • No receptor identified at this stage
   • Single cell line
   • Mechanism of UVB-induced secretion not defined
4. 2018 Medium

   Loss- and gain-of-function established that LGI3 promotes keratinocyte differentiation specifically through Akt, distinguishing it from MAPK signaling and confirming an in vivo skin role.

   Evidence siRNA knockdown, recombinant LGI3 treatment, PI3K inhibitor (LY294002), and LGI3-knockout mouse skin analysis

   PMID:30091803

   Open questions at the time

   • Receptor not identified in this study
   • Single lab
   • Connection to the secretion machinery unresolved
5. 2019 Medium

   This work resolved both how LGI3 secretion is controlled and what receptor it engages in skin, identifying a TRIF–NF-κB transcriptional circuit and ADAM22 as an LGI3 receptor.

   Evidence ELISA, TRIF-specific NF-κB inhibition, promoter binding assay, co-IP, flow cytometry, and immunocytochemistry in HaCaT cells

   PMID:31627033

   Open questions at the time

   • Direct binding affinity not measured
   • ADAM22 link to downstream Akt signaling not formally connected
   • Single cell line
6. 2022 Medium

   LGI3 signaling was extended to keratinocyte migration in a high-glucose setting, mapping a specific Akt–FOXO1–FAK–β-catenin output.

   Evidence siRNA knockdown, wound-healing migration assay, signaling Western blots, and PI3K inhibition in HaCaT cells

   PMID:35751164

   Open questions at the time

   • Receptor not identified
   • Single lab and cell line
   • In vivo relevance to diabetic wound healing not tested
7. 2023 High

   In vivo genetics defined the core neural function of LGI3: acting with LGI2 through axonal ADAM23 to cluster and stabilize juxtaparanodal Kv1 channels that set the axonal refractory period and burst firing.

   Evidence ADAM23 knockout mice, immunohistochemistry/electron microscopy of Kv1 localization, electrophysiology, and LGI2/LGI3–ADAM23 interaction studies

   PMID:36828548

   Open questions at the time

   • Relative contributions of LGI2 vs. LGI3 not fully separated
   • Cell source of LGI3 not defined here
   • Structural basis of LGI–ADAM23–Kv1 assembly unknown
8. 2024 High

   Cell-source and proteomic work established that oligodendrocyte-secreted LGI3 forms juxtaparanodal nanoclusters via ADAM23 to assemble Kv1 channels and support short-term synaptic plasticity, and tied a secretion-defective missense variant to disease.

   Evidence Epitope-tagged Lgi3 knockin proteomics, Lgi3 knockout phenotyping, imaging, electrophysiology, and secretion assay of a missense variant in mice

   PMID:38194969

   Open questions at the time

   • Disease mechanism downstream of defective secretion not fully traced
   • Stoichiometry of the LGI3–ADAM23–Kv1 nanocluster unresolved
   • Regulation of oligodendrocyte LGI3 secretion unknown
9. 2025 Medium

   A new functional axis placed LGI3 as a TFE3-fusion transcriptional target that stabilizes GEMIN6 to elevate AURKB, defining a pro-tumorigenic role in TFE3-rearranged renal cell carcinoma.

   Evidence ChIP/promoter binding, co-IP, ubiquitination assay, knockdown with proliferation/migration/invasion readouts, and organoid drug sensitivity assays

   PMID:40849584

   Open questions at the time

   • Direct vs. indirect LGI3–GEMIN6 binding not resolved
   • Mechanism by which LGI3 blocks GEMIN6 ubiquitination unknown
   • Single lab
10. 2026 Medium

    LGI3 was shown to modulate cardiac excitability by joining the atrial KV1.5 channelosome and interfering with KV1.5/KVβ assembly to reduce IKur.

    Evidence Co-IP in human atrial tissue and HEK293 cells, patch clamp, surface expression assay, with an AAV9 Lgi4 overexpression comparator

    PMID:41854369

    Open questions at the time

    • Lgi3-specific cardiac evidence partially inferred alongside Lgi4 data
    • In vivo cardiac LGI3 loss-of-function not tested
    • Role of a cardiac ADAM partner not established

• It remains unknown how LGI3's distinct activities — ADAM23/Kv1 channel organization, ADAM22/PI3K–Akt signaling, flotillin-1-dependent trafficking, and intracellular GEMIN6 stabilization — are reconciled mechanistically, and whether a single secreted form underlies all of them.
• No structural model of LGI3 bound to any ADAM receptor
• Whether the nuclear/intracellular GEMIN6-stabilizing pool is the same protein as the secreted ligand is undefined
• No unifying account of receptor choice across tissues