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

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

doi:10.1186/s13619-026-00289-7

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

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	17
Journal	Cell Regeneration
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13619-026-00289-7
State	Published - May 19 2026

Keywords

Cell recovery
ESCRT-III
Necroptosis
Plasma membrane damage
Plasma membrane integrity pathway
Plasma membrane repair
Programmed cell death
Tollip

ASJC Scopus subject areas

Developmental Biology
Cell Biology

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10.1186/s13619-026-00289-7

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title = "Tollip antagonizes ESCRT-III-mediated plasma membrane repair and cell recovery",

abstract = "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.",

keywords = "Cell recovery, ESCRT-III, Necroptosis, Plasma membrane damage, Plasma membrane integrity pathway, Plasma membrane repair, Programmed cell death, Tollip",

author = "Ferrick, \{Julia M.\} and Xinan Meng and Emily Morgan and Anthony Kalvi and Zhen Li and Chaoqun Li and Chang, \{Chao Yuan\} and Suhong Xu and Gong, \{Yi Nan\}",

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doi = "10.1186/s13619-026-00289-7",

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AU - Ferrick, Julia M.

AU - Meng, Xinan

AU - Morgan, Emily

AU - Kalvi, Anthony

AU - Li, Zhen

AU - Li, Chaoqun

AU - Chang, Chao Yuan

AU - Xu, Suhong

AU - Gong, Yi Nan

PY - 2026/5/19

Y1 - 2026/5/19

N2 - 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.

AB - 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.

KW - Cell recovery

KW - ESCRT-III

KW - Necroptosis

KW - Plasma membrane damage

KW - Plasma membrane integrity pathway

KW - Plasma membrane repair

KW - Programmed cell death

KW - Tollip

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

Abstract

Keywords

ASJC Scopus subject areas

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