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<p>The trafficking of AMPA receptors (AMPARs), including internalization, recycling, and membrane reinsertion, is critical for maintaining synaptic plasticity. Our previous work showed that the microtubule-severing protein Spastin regulates AMPAR surface expression, but the underlying mechanisms remain to be fully elucidated. Here, we demonstrate that deSUMOylated Spastin (Spastin-K427R) enhanced GluA1 recycling and membrane reinsertion and is associated with dendritic spine maturation and excitatory synaptic transmission. Overexpression of Spastin-K427R increased surface GluA1 expression, spine density, and miniature excitatory synaptic currents (mEPSC) amplitude and frequency, with stronger effects than wild-type Spastin. While wild-type Spastin directed GluA1 to both recycling and late endosomes, Spastin-K427R preferentially promoted its localization to Syntaxin 13-associated recycling endosomes and reduced LAMP1-associated degradation. We further identified IST1, an ESCRT-III complex component, as a key mediator of Spastin’s effect. Co-overexpression of IST1 with Spastin enhanced synaptic transmission and spine maturation, whereas IST1 knockdown reduced GluA1 surface levels and abolished Spastin’s effects. Notably, Spastin-K427R exhibited enhanced binding to IST1 than wild-type Spastin. These findings reveal a post-translational mechanism by which the deSUMOylation of Spastin facilitates IST1-dependent AMPAR recycling, contributing to synaptic plasticity regulation.</p> Graphical Abstract <p></p>

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DeSUMOylation of Spastin Enhances AMPA Receptor Recycling and Synaptic Plasticity via IST1-Dependent Endosomal Sorting

  • 期刊论文

  • 发表日期：

    2025年11月26日

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  • Jiong Li,
  • Bingyu Ren,
  • Yichen Yin,
  • Kedong Chen,
  • Meiying Chen,
  • Guangyin Yu,
  • Guoqing Guo,
  • Jifeng Zhang,
  • Caihui Cha,
  • Laijian Wang

摘要

The trafficking of AMPA receptors (AMPARs), including internalization, recycling, and membrane reinsertion, is critical for maintaining synaptic plasticity. Our previous work showed that the microtubule-severing protein Spastin regulates AMPAR surface expression, but the underlying mechanisms remain to be fully elucidated. Here, we demonstrate that deSUMOylated Spastin (Spastin-K427R) enhanced GluA1 recycling and membrane reinsertion and is associated with dendritic spine maturation and excitatory synaptic transmission. Overexpression of Spastin-K427R increased surface GluA1 expression, spine density, and miniature excitatory synaptic currents (mEPSC) amplitude and frequency, with stronger effects than wild-type Spastin. While wild-type Spastin directed GluA1 to both recycling and late endosomes, Spastin-K427R preferentially promoted its localization to Syntaxin 13-associated recycling endosomes and reduced LAMP1-associated degradation. We further identified IST1, an ESCRT-III complex component, as a key mediator of Spastin’s effect. Co-overexpression of IST1 with Spastin enhanced synaptic transmission and spine maturation, whereas IST1 knockdown reduced GluA1 surface levels and abolished Spastin’s effects. Notably, Spastin-K427R exhibited enhanced binding to IST1 than wild-type Spastin. These findings reveal a post-translational mechanism by which the deSUMOylation of Spastin facilitates IST1-dependent AMPAR recycling, contributing to synaptic plasticity regulation.

Graphical Abstract