Scholarlink

<p>Necrosome assembly is essential for necroptosis, a process implicated in neurodegeneration, ischemic injury, and inflammatory diseases. Yet the spatiotemporal rules governing this assembly remain elusive. Leveraging quantitative STORM and mathematical modeling, we define an approximately 3:1 ratio of RIP3 to RIP1 in necrosomes as the optimal stoichiometry for necroptosis, enabling signal amplification and a threshold response. Surprisingly, excessive RIP3 oligomerization attenuates signaling, acting as an intrinsic size control mechanism. RIP3 assembly is dynamically regulated: it is constrained by stimulation and RIP1, promoted by RIP3 itself, and unexpectedly limited by downstream MLKL. A complementary balance between necrosome quantity and RIP3 assembly degree ensures efficient MLKL phosphorylation. In contrast, Caspase-8 assembly is limited by c-FLIP and recruited linearly by RIP1, while its distinct behavior from RIP3 underlies the biphasic necroptotic response to RIP1. These findings uncover the flexible, multi-strategic nature of signalosomes and offer valuable insights for therapeutic and synthetic biology.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Decoding necrosome assembly: harmonizing signal amplification and attenuation through optimal RIP3 stoichiometry

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月23日

查看全文
  • Xiang Li,
  • Yating Cao,
  • Fei Xu,
  • Yiting Zhang,
  • Yue Kong,
  • Chengjie Lan,
  • Rongfeng Zhu,
  • Cheng Lin,
  • Chuan-Qi Zhong,
  • Zhilong Liu,
  • Hong Qi,
  • Yichuan Huang,
  • Yunshan Xiao,
  • Gui-Quan Sun,
  • Jianwei Shuai,
  • Xin Chen

摘要

Necrosome assembly is essential for necroptosis, a process implicated in neurodegeneration, ischemic injury, and inflammatory diseases. Yet the spatiotemporal rules governing this assembly remain elusive. Leveraging quantitative STORM and mathematical modeling, we define an approximately 3:1 ratio of RIP3 to RIP1 in necrosomes as the optimal stoichiometry for necroptosis, enabling signal amplification and a threshold response. Surprisingly, excessive RIP3 oligomerization attenuates signaling, acting as an intrinsic size control mechanism. RIP3 assembly is dynamically regulated: it is constrained by stimulation and RIP1, promoted by RIP3 itself, and unexpectedly limited by downstream MLKL. A complementary balance between necrosome quantity and RIP3 assembly degree ensures efficient MLKL phosphorylation. In contrast, Caspase-8 assembly is limited by c-FLIP and recruited linearly by RIP1, while its distinct behavior from RIP3 underlies the biphasic necroptotic response to RIP1. These findings uncover the flexible, multi-strategic nature of signalosomes and offer valuable insights for therapeutic and synthetic biology.