14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice

DOI HANDLE Web Site Web Site 2 Citations 68 References Open Access
  • Yokoi, Norihiko
    Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
  • Fukata, Yuko
    Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
  • Okatsu, Kei
    Department of Chemistry, Graduate School of Science, Kyoto University
  • Yamagata, Atsushi
    RIKEN Center for Biosystems Dynamics Research
  • Liu, Yan
    Department of Chemistry, Graduate School of Science, Kyoto University
  • Sanbo, Makoto
    Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
  • Miyazaki, Yuri
    Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
  • Goto, Teppei
    Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
  • Abe, Manabu
    Department of Animal Model Development, Brain Research Institute, Niigata University
  • Kassai, Hidetoshi
    Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
  • Sakimura, Kenji
    Department of Animal Model Development, Brain Research Institute, Niigata University
  • Meijer, Dies
    Centre for Discovery Brain Sciences, University of Edinburgh
  • Hirabayashi, Masumi
    Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies); Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
  • Fukai, Shuya
    Department of Chemistry, Graduate School of Science, Kyoto University
  • Fukata, Masaki
    Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)

Abstract

What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that ∼50% of LGI1 and ∼10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment.

Journal

  • Cell Reports

    Cell Reports 37 (11), 110107-, 2021-12

    Elsevier BV

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