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<p>The soluble <i>N</i>-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion.</p>

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Munc18 modulates syntaxin phase separation to promote exocytosis

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Qing Pei,
  • Qixin Chen,
  • Zhiqi Tian,
  • Le Zhu,
  • Yang Chen,
  • Jihong Gong,
  • Shen Wang,
  • Yijuan Xiang,
  • John S. Khamo,
  • Jiaqi Fan,
  • Yi Rong,
  • Yi Yu,
  • Yuyang Qin,
  • Shiping Wu,
  • Youssef Faragalla,
  • Peng Cao,
  • Kai Zhang,
  • Ying Lai,
  • Ling-Gang Wu,
  • Cong Ma,
  • Xiaofei Yang,
  • Jiajie Diao

摘要

The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin mediates neuronal exocytosis and self-assembles into large clusters in the plasma membrane. The formation and function of these clusters, and whether they promote or inhibit synaptic-vesicle fusion, remain unclear. Here using optogenetic control of syntaxin clustering in vitro and in vivo, as a light-inducible gain-of-function assay, we show that light-enhanced clustering reduces both spontaneous and triggered vesicle fusion, and this impairs mouse hunting behavior. Cluster formation is induced by liquid–liquid phase separation (LLPS) of the SNARE domain of syntaxin. For the regulatory mechanism, Munc18, which is known to alter syntaxin conformation, acts to reduce LLPS for cluster formation, thereby promoting active syntaxin. These results suggest that exocytosis regulation involves LLPS-induced syntaxin clusters that serve as a syntaxin reservoir from which Munc18 captures syntaxin monomers to form a syntaxin–Munc18 complex, setting the stage for efficient fusion.