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<p>Cells can recover from sub-lethal necrosis by repairing plasma-membrane (PM) rupture through the ESCRT-III machinery, but how this process is regulated remains unknown. Here, we identify Toll-interacting protein (Tollip) as a conserved negative regulator for ESCRT-III–mediated PM repair. Quantitative proteomics revealed the enrichment of Tollip at damaged PM. Additionally, microscopy assays in mammalian cells and <i>C. elegans</i> confirmed the recruitment of Tollip to PM injury sites. Tollip deficiency augmented ESCRT-III assembly, improved long-term cell survival after sub-lethal PM damage, and enhanced PM repair, whereas Tollip overexpression suppressed these processes. Tollip translocation occurred independently of Ca<sup>2</sup>⁺ influx, different from ESCRT-III. Functionally, by limiting PM repair and maintaining sub-lethal PM integrity loss, Tollip ensured optimal chemokine and cytokine production from the plasma-membrane-integrity (PMI) pathway, which is directly triggered by PM ruptures. Thus, Tollip acts as a molecular rheostat that links membrane damage repair and cell recovery to immune signaling.</p>

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Tollip antagonizes ESCRT-III-mediated plasma membrane repair and cell recovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Julia M. Ferrick,
  • Xinan Meng,
  • Emily Morgan,
  • Anthony Kalvi,
  • Zhen Li,
  • Chaoqun Li,
  • Chao-Yuan Chang,
  • Suhong Xu,
  • Yi-Nan Gong

摘要

Cells can recover from sub-lethal necrosis by repairing plasma-membrane (PM) rupture through the ESCRT-III machinery, but how this process is regulated remains unknown. Here, we identify Toll-interacting protein (Tollip) as a conserved negative regulator for ESCRT-III–mediated PM repair. Quantitative proteomics revealed the enrichment of Tollip at damaged PM. Additionally, microscopy assays in mammalian cells and C. elegans confirmed the recruitment of Tollip to PM injury sites. Tollip deficiency augmented ESCRT-III assembly, improved long-term cell survival after sub-lethal PM damage, and enhanced PM repair, whereas Tollip overexpression suppressed these processes. Tollip translocation occurred independently of Ca2⁺ influx, different from ESCRT-III. Functionally, by limiting PM repair and maintaining sub-lethal PM integrity loss, Tollip ensured optimal chemokine and cytokine production from the plasma-membrane-integrity (PMI) pathway, which is directly triggered by PM ruptures. Thus, Tollip acts as a molecular rheostat that links membrane damage repair and cell recovery to immune signaling.