LGI3

LGI3 is a secreted leucine-rich repeat protein that organizes ion channel complexes and activates PI3K/Akt signaling across multiple tissue contexts. In myelinated axons, LGI3 is released from oligodendrocytes, binds the receptor ADAM23, and is essential for juxtaparanodal clustering of Kv1 potassium channels, thereby controlling the axonal refractory period and short-term synaptic plasticity (PMID:36828548, PMID:38194969). In keratinocytes, LGI3 acts as an autocrine/paracrine cytokine that signals through ADAM22 and activates PI3K/Akt to promote cell survival (via MDM2-mediated p53 degradation), differentiation, and migration (PMID:22741557, PMID:30091803, PMID:31627033). In the heart, LGI3 is a component of the KV1.5 channelosome, where it impairs KV1.5–KVβ interaction and reduces the ultra-rapid delayed rectifier current IKur (PMID:41854369); in renal cell carcinoma, it stabilizes GEMIN6 by blocking its ubiquitination to promote AURKB expression and tumor growth (PMID:40849584).

1. 2007 Medium

   Initial localization studies established that LGI3 resides at plasma membranes and in nuclei of neural cells and co-localizes with endocytic and lipid raft markers, placing LGI3 in a membrane-associated signaling context before any functional role was known.

   Evidence Immunohistochemistry, subcellular fractionation, and co-localization in aged monkey brain and rat astrocyte cultures

   PMID:17387609 PMID:17786549

   Open questions at the time

   • No functional assay for endocytic activity
   • Co-localization with Aβ does not demonstrate direct interaction
   • Role in astrocytes versus neurons not resolved
2. 2010 Medium

   Discovery that LGI3 interacts with and reciprocally stabilizes flotillin-1 revealed a role in intracellular vesicular trafficking, as loss of the LGI3/flotillin-1 complex redirected APP to late endosomes and disrupted exosome formation.

   Evidence Co-immunoprecipitation and siRNA knockdown with Western blot in neural cell lines

   PMID:20461023

   Open questions at the time

   • Single-lab observation without independent replication
   • Mechanism of stabilization (direct binding site) unknown
   • Relevance to in vivo APP processing not tested
3. 2012 Medium

   Identification of LGI3 as a UVB-induced secreted factor from keratinocytes that activates Akt→MDM2→p53 degradation established LGI3 as an autocrine survival cytokine outside the nervous system.

   Evidence ELISA for secreted LGI3, recombinant protein treatment, phospho-Akt and p53 Western blot in human keratinocytes

   PMID:22741557

   Open questions at the time

   • Receptor identity was not determined in this study
   • In vivo relevance to skin UV protection not shown
4. 2018 Medium

   Using LGI3-knockout mice and pharmacological inhibition, LGI3 was shown to selectively activate PI3K/Akt (not ERK, p38, or JNK) to drive keratinocyte differentiation, providing genetic validation of the pathway.

   Evidence LGI3-knockout mouse, siRNA, LY294002 inhibition, involucrin expression in skin

   PMID:30091803

   Open questions at the time

   • Single-lab genetic model
   • Downstream transcriptional targets of Akt in differentiation not mapped
5. 2019 Medium

   The receptor for secreted LGI3 in keratinocytes was identified as ADAM22, and LGI3 transcription was shown to be driven by NF-κB via TRIF-dependent signaling, completing the stimulus–secretion–receptor circuit.

   Evidence Co-immunoprecipitation of LGI3–ADAM22, NF-κB ChIP on LGI3 promoter, LPS-stimulated keratinocytes

   PMID:31627033

   Open questions at the time

   • ADAM22 interaction shown by Co-IP without domain mapping
   • Whether ADAM22 is the sole receptor in skin not tested
6. 2022 Medium

   LGI3 was found to rescue high-glucose-impaired keratinocyte migration by activating Akt→FOXO1/FAK→β-catenin, extending its PI3K/Akt signaling role to wound healing contexts.

   Evidence Wound closure assay, siRNA knockdown, pharmacological inhibition with LY294002

   PMID:35751164

   Open questions at the time

   • In vivo diabetic wound healing model not performed
   • Single-lab study
7. 2023 High

   Genetic studies in mice demonstrated that LGI3 (with LGI2) binds ADAM23 and is essential for juxtaparanodal Kv1 channel clustering; loss of LGI3–ADAM23 interaction abolished Kv1 accumulation and altered the refractory period, enabling pathological high-frequency firing.

   Evidence Genetic knockout/knockin mouse models, immunohistochemistry, electrophysiology (refractory period)

   PMID:36828548

   Open questions at the time

   • Relative contributions of LGI2 versus LGI3 not fully delineated
   • Structural basis of LGI3–ADAM23 binding unknown
8. 2024 High

   In vivo proteomics using epitope-tagged Lgi3 knockin mice established that LGI3 is uniquely secreted from oligodendrocytes and selectively co-assembles with Kv1 channels via ADAM23, and that its loss suppresses Kv1-channel-mediated short-term synaptic plasticity.

   Evidence AP-MS proteomics from knockin mice, LGI3-null electrophysiology (short-term plasticity), missense variant secretion assay

   PMID:38194969

   Open questions at the time

   • Whether LGI3 acts on unmyelinated axons is unknown
   • Mechanism by which LGI3 stabilizes the Kv1–ADAM23 complex at the molecular level not resolved
9. 2025 High

   LGI3 was identified as a component of the cardiac KV1.5 channelosome that impairs KV1.5–KVβ association, partially reverses N-type inactivation, and reduces IKur amplitude and KV1.5 surface expression, establishing a cardiac electrophysiological function.

   Evidence Co-immunoprecipitation in human atrial tissue, patch-clamp electrophysiology, AAV-mediated cardiac gene transfer in mice

   PMID:41854369

   Open questions at the time

   • Whether LGI3 modulation of KV1.5 is relevant to atrial fibrillation in vivo not tested
   • Mechanism of reduced surface expression (trafficking vs. degradation) not distinguished
10. 2025 Medium

    In TFE3-fusion renal cell carcinoma, LGI3 was identified as a direct TFE3 transcriptional target that stabilizes GEMIN6 by blocking its ubiquitination, promoting AURKB mRNA maturation and tumor progression — the first oncogenic mechanism described for LGI3.

    Evidence ChIP, co-immunoprecipitation (LGI3–GEMIN6), ubiquitination assay, organoid growth assay

    PMID:40849584

    Open questions at the time

    • Single-lab study; not independently replicated
    • Whether LGI3 stabilizes GEMIN6 through direct ubiquitin competition or indirect E3-ligase modulation is unknown
    • Generalizability to non-TFE3-fusion cancers not addressed

• No structural model of LGI3 in complex with any receptor (ADAM22, ADAM23, KV1.5) exists, and whether LGI3's diverse tissue-specific functions share a common molecular mechanism of action through metalloprotease-family receptors remains an open question.
• No crystal or cryo-EM structure of LGI3 or LGI3–receptor complex
• Mechanism by which LGI3 discriminates between ADAM22 and ADAM23 in different tissues is unknown
• In vivo physiological roles in tissues beyond brain, skin, and heart have not been explored